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Charitos IA, Scacco S, Cotoia A, Castellaneta F, Castellana G, Pasqualotto F, Venneri M, Ferrulli A, Aliani M, Santacroce L, Carone M. Intestinal Microbiota Dysbiosis Role and Bacterial Translocation as a Factor for Septic Risk. Int J Mol Sci 2025; 26:2028. [PMID: 40076650 PMCID: PMC11900423 DOI: 10.3390/ijms26052028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 02/18/2025] [Accepted: 02/22/2025] [Indexed: 03/14/2025] Open
Abstract
The human immune system is closely linked to microbiota such as a complex symbiotic relationship during the coevolution of vertebrates and microorganisms. The transfer of microorganisms from the mother's microbiota to the newborn begins before birth during gestation and is considered the initial phase of the intestinal microbiota (IM). The gut is an important site where microorganisms can establish colonies. The IM contains polymicrobial communities, which show complex interactions with diet and host immunity. The tendency towards dysbiosis of the intestinal microbiota is influenced by local but also extra-intestinal factors such as inflammatory processes, infections, or a septic state that can aggravate it. Pathogens could trigger an immune response, such as proinflammatory responses. In addition, changes in the host immune system also influence the intestinal community and structure with additional translocation of pathogenic and non-pathogenic bacteria. Finally, local intestinal inflammation has been found to be an important factor in the growth of pathogenic microorganisms, particularly in its role in sepsis. The aim of this article is to be able to detect the current knowledge of the mechanisms that can lead to dysbiosis of the intestinal microbiota and that can cause bacterial translocation with a risk of infection or septic state and vice versa.
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Affiliation(s)
- Ioannis Alexandros Charitos
- Pneumology and Respiratory Rehabilitation Unit, Istituti Clinici Scientifici Maugeri IRCCS, “Istitute” of Bari, 70124 Bari, Italy; (I.A.C.); (G.C.); (F.P.); (M.A.); (M.C.)
- Doctoral School, Applied Neurosciences, University of Bari (UNIBA), 70124 Bari, Italy
| | - Salvatore Scacco
- Dipartimento di Biomedicina Traslazionale e Neuroscienze (DiBraiN), Scuola di Medicina, Università Degli Studi di Bari, Aldo Moro, 70124 Bari, Italy;
- U.O. Medicina, Ospedale Mater Dei-CBH, 70125 Bari, Italy
| | - Antonella Cotoia
- Department of Intensive Care, University Hospital of Foggia, 71121 Foggia, Italy
| | - Francesca Castellaneta
- U.O.C. Servizio di Immunoematologia e Medicina Trasfusionale—S.I.M.T. Ospedale Di Venere, 70131 Bari, Italy;
| | - Giorgio Castellana
- Pneumology and Respiratory Rehabilitation Unit, Istituti Clinici Scientifici Maugeri IRCCS, “Istitute” of Bari, 70124 Bari, Italy; (I.A.C.); (G.C.); (F.P.); (M.A.); (M.C.)
| | - Federico Pasqualotto
- Pneumology and Respiratory Rehabilitation Unit, Istituti Clinici Scientifici Maugeri IRCCS, “Istitute” of Bari, 70124 Bari, Italy; (I.A.C.); (G.C.); (F.P.); (M.A.); (M.C.)
- Department of Public Health and Infectious Diseases, Pulmonary Division, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Via del Policlinico 155, 00155 Rome, Italy
| | - Maria Venneri
- Genomics and Proteomics Laboratory, Istituti Clinici Scientifici Maugeri IRCCS, “Istitute” of Bari, 70124 Bari, Italy; (M.V.); (A.F.)
| | - Angela Ferrulli
- Genomics and Proteomics Laboratory, Istituti Clinici Scientifici Maugeri IRCCS, “Istitute” of Bari, 70124 Bari, Italy; (M.V.); (A.F.)
| | - Maria Aliani
- Pneumology and Respiratory Rehabilitation Unit, Istituti Clinici Scientifici Maugeri IRCCS, “Istitute” of Bari, 70124 Bari, Italy; (I.A.C.); (G.C.); (F.P.); (M.A.); (M.C.)
| | - Luigi Santacroce
- Interdisciplinary Department of Medicine, Section of Microbiology and Virology, School of Medicine, The University of Bari, 70124 Bari, Italy;
| | - Mauro Carone
- Pneumology and Respiratory Rehabilitation Unit, Istituti Clinici Scientifici Maugeri IRCCS, “Istitute” of Bari, 70124 Bari, Italy; (I.A.C.); (G.C.); (F.P.); (M.A.); (M.C.)
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Shi H, Sun J, Sun Y, Wu J, Jiang G, Xu Z, Shi X, Fang M. Intestinal Epithelial Cell-specific Knockout of METTL3 Aggravates Intestinal Inflammation in CLP Mice by Weakening the Intestinal Barrier. Curr Pharm Biotechnol 2025; 26:80-91. [PMID: 38482615 DOI: 10.2174/0113892010271970240202054245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/19/2023] [Accepted: 12/28/2023] [Indexed: 11/30/2024]
Abstract
BACKGROUND Many studies have demonstrated that the expression of methyltransferase- like 3 (METTL3) is altered in various inflammatory diseases. Its specific mechanistic role in the intestinal inflammatory response during sepsis remains limited and requires further investigation. OBJECTIVES Explore the potential mechanism of METTL3 in the intestinal inflammatory response during sepsis. MATERIALS AND METHODS Immunohistochemical analysis was utilized to detect the expression of METTL3 in the necrotic intestine of patients with intestinal necrosis and the small intestine of cecal ligation and puncture (CLP) mice. Mice were subjected to the CLP and Sham surgeries, intestine tissue was harvested and performed HE staining, and ELISA to examine intestinal inflammatory responses, while TUNEL staining was applied to detect intestinal cell apoptosis. Additionally, ELISA was used to detect diamine oxidase (DAO) and intestinal fatty acid binding protein (I-FABP) levels in intestinal tissue. Immunohistochemistry and RT-qPCR were also employed to examine the mRNA and protein expression levels of Zona Occludens 1 (ZO-1) and Claudin-1. Finally, transcriptomic sequencing was performed on the small intestine tissues of METTL3 Knock-out (KO) and Wild-type (WT) mice in response to sepsis. RESULTS METTL3 exhibited lower expression level in the necrotic intestine of patients and the small intestine of CLP mice. Loss of METTL3 in CLP mice triggered significantly higher expression of TNF-α and IL-18, down-regulated expression of ZO-1 and claudin-1, and decreased expression of DAO and I-FABP in the intestinal tissue. KEGG enrichment analysis showed that the differential genes were significantly enriched in immune-related pathways. CONCLUSION This study reveals a novel mechanism responsible for exacerbated intestinal inflammation orchestrated by METTL3. Particularly, METTL3 null mice displayed decreased ZO- 1 and Claudin-1 expression, which largely hampered intestinal epithelial barrier function, resulting in bacterial and toxin translocation and intestinal immune activation and inflammation against sepsis.
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Affiliation(s)
- Hongzhou Shi
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Jiahui Sun
- School of Public Health, Southeast University, Nanjing, 210000, China
| | - Yaya Sun
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Junjie Wu
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Guangqing Jiang
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Zhaiyue Xu
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Xin Shi
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
| | - Miao Fang
- Department of General Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 21000, China
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Li Z, Wan M, Wang M, Duan J, Jiang S. Modulation of gut microbiota on intestinal permeability: A novel strategy for treating gastrointestinal related diseases. Int Immunopharmacol 2024; 137:112416. [PMID: 38852521 DOI: 10.1016/j.intimp.2024.112416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/07/2024] [Accepted: 06/03/2024] [Indexed: 06/11/2024]
Abstract
Accumulating evidence emphasizes the critical reciprocity between gut microbiota and intestinal barrier function in maintaining the gastrointestinal homeostasis. Given the fundamental role caused by intestinal permeability, which has been scrutinized as a measurable potential indicator of perturbed barrier function in clinical researches, it seems not surprising that recent decades have been marked by augmented efforts to determine the interaction between intestinal microbes and permeability of the individual. However, despite the significant progress in characterizing intestinal permeability and the commensal bacteria in the intestine, the mechanisms involved are still far from being thoroughly revealed. In the present review, based on multiomic methods, high-throughput sequencing and molecular biology techniques, the impacts of gut microbiota on intestinal permeability as well as their complex interaction networks are systematically summarized. Furthermore, the diseases related to intestinal permeability and main causes of changes in intestinal permeability are briefly introduced. The purpose of this review is to provide a novel prospection to elucidate the correlation between intestinal microbiota and permeability, and to explore a promising solution for diagnosis and treatment of gastrointestinal related diseases.
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Affiliation(s)
- Zhuotong Li
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, PR China
| | - Meiyu Wan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, PR China
| | - Mingyang Wang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, PR China
| | - Jinao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, PR China
| | - Shu Jiang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, PR China.
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Hua T, Lu Z, Wang M, Zhang Y, Chu Y, Liu Y, Xiao W, Zhou W, Cui X, Shi W, Zhang J, Yang M. Shenfu injection alleviate gut ischemia/reperfusion injury after severe hemorrhagic shock through improving intestinal microcirculation in rats. Heliyon 2024; 10:e31377. [PMID: 38845930 PMCID: PMC11153106 DOI: 10.1016/j.heliyon.2024.e31377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 05/13/2024] [Accepted: 05/15/2024] [Indexed: 06/09/2024] Open
Abstract
Background Shenfu (SF) injection, a traditional Chinese medication, would improve microcirculation in cardiogenic shock and infectious shock. This study was aimed to explore the therapeutic potential of the SF injection in gut ischemia-reperfusion (I/R) injury after severe hemorrhagic shock (SHS) and resuscitation. Furthermore, we also investigated the optimal adm？ inistration timing. Methods Twenty-four male SD rats were randomly divided into four groups: Sham group (sham, n = 6), Control group (n = 6), SF injection group (SF, n = 6), and Delayed Shenfu injection administration group (SF-delay, n = 6). In SHS and resuscitation model, rats were induced by blood draw to a mean arterial pressure (MAP) of 40 ± 5 mmHg within 1 h and then maintained for 40 min; HR, MAP 'were recorded, microcirculation index [De Backer score, perfused small vessel density (PSVD), total vessel density (TVD), microcirculation flow index score (MFI), flow heterogeneity index (HI)] were analyzed. The blood gas index was detected, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), diamine oxidase (DAO), malondialdehyde (MDA) were measured by ELISA; ZO-1, and claudin-1 were measured by Western blotting. In addition, hematoxylin-eosin (HE) and periodic acid schiff (PAS) staining pathological sections of the intestinal mucosal tissues were also performed. Results SF injection increased the MAP, relieved the metabolic acidosis degree associated with the hypoperfusion, and improved the intestinal microcirculatory density and perfusion quality after I/R injury. The expression of DAO, MDA in intestinal tissue, and plasma IL-6, TNF-α significantly decreased in the SF injection group compared to the control group. The concentration of ZO-1 and claudin-1 is also higher in the SF injection group. In addition, the HE and PAS staining results also showed that SF injection could decrease mucosal damage and maintain the structure. In the SF-delay group, the degree of intestinal tissue damage was intermediate between that of the control group and SF injection group. Conclusions SF injection protect the intestine from I/R injury induced by SHS and resuscitation, the mechanism of which might be through improving intestinal microcirculation, reducing the excessive release of inflammatory factors and increasing intestinal mucosal permeability. Furthermore, the protection effect is more pronounced if administration during the initial resuscitation phase.
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Affiliation(s)
- Tianfeng Hua
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Zongqing Lu
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Minjie Wang
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Yijun Zhang
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Yuqian Chu
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Yue Liu
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Cardiovascular Disease Center of Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, PR China
| | - Wenyan Xiao
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Wuming Zhou
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Xuanxuan Cui
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Wei Shi
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Jin Zhang
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
| | - Min Yang
- The Second Department of Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
- Laboratory of Cardiopulmonary Resuscitation and Critical Care, The Second Affiliated Hospital of Anhui Medical University, Anhui, Hefei, 230601, PR China
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Coccolini F, Sartelli M, Sawyer R, Rasa K, Viaggi B, Abu-Zidan F, Soreide K, Hardcastle T, Gupta D, Bendinelli C, Ceresoli M, Shelat VG, Broek RT, Baiocchi GL, Moore EE, Sall I, Podda M, Bonavina L, Kryvoruchko IA, Stahel P, Inaba K, Montravers P, Sakakushev B, Sganga G, Ballestracci P, Malbrain MLNG, Vincent JL, Pikoulis M, Beka SG, Doklestic K, Chiarugi M, Falcone M, Bignami E, Reva V, Demetrashvili Z, Di Saverio S, Tolonen M, Navsaria P, Bala M, Balogh Z, Litvin A, Hecker A, Wani I, Fette A, De Simone B, Ivatury R, Picetti E, Khokha V, Tan E, Ball C, Tascini C, Cui Y, Coimbra R, Kelly M, Martino C, Agnoletti V, Boermeester MA, De'Angelis N, Chirica M, Biffl WL, Ansaloni L, Kluger Y, Catena F, Kirkpatrick AW. Source control in emergency general surgery: WSES, GAIS, SIS-E, SIS-A guidelines. World J Emerg Surg 2023; 18:41. [PMID: 37480129 PMCID: PMC10362628 DOI: 10.1186/s13017-023-00509-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 06/30/2023] [Indexed: 07/23/2023] Open
Abstract
Intra-abdominal infections (IAI) are among the most common global healthcare challenges and they are usually precipitated by disruption to the gastrointestinal (GI) tract. Their successful management typically requires intensive resource utilization, and despite the best therapies, morbidity and mortality remain high. One of the main issues required to appropriately treat IAI that differs from the other etiologies of sepsis is the frequent requirement to provide physical source control. Fortunately, dramatic advances have been made in this aspect of treatment. Historically, source control was left to surgeons only. With new technologies non-surgical less invasive interventional procedures have been introduced. Alternatively, in addition to formal surgery open abdomen techniques have long been proposed as aiding source control in severe intra-abdominal sepsis. It is ironic that while a lack or even delay regarding source control clearly associates with death, it is a concept that remains poorly described. For example, no conclusive definition of source control technique or even adequacy has been universally accepted. Practically, source control involves a complex definition encompassing several factors including the causative event, source of infection bacteria, local bacterial flora, patient condition, and his/her eventual comorbidities. With greater understanding of the systemic pathobiology of sepsis and the profound implications of the human microbiome, adequate source control is no longer only a surgical issue but one that requires a multidisciplinary, multimodality approach. Thus, while any breach in the GI tract must be controlled, source control should also attempt to control the generation and propagation of the systemic biomediators and dysbiotic influences on the microbiome that perpetuate multi-system organ failure and death. Given these increased complexities, the present paper represents the current opinions and recommendations for future research of the World Society of Emergency Surgery, of the Global Alliance for Infections in Surgery of Surgical Infection Society Europe and Surgical Infection Society America regarding the concepts and operational adequacy of source control in intra-abdominal infections.
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Affiliation(s)
- Federico Coccolini
- General, Emergency and Trauma Surgery Dept., Pisa University Hospital, Via Paradisia, 56124, Pisa, Italy.
| | | | - Robert Sawyer
- Department of Surgery, Western Michigan University Homer Stryker MD School of Medicine, Kalamazoo, MI, USA
| | | | - Bruno Viaggi
- ICU Dept., Careggi University Hospital, Florence, Italy
| | - Fikri Abu-Zidan
- Department of Surgery, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Kjetil Soreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, University of Bergen, Bergen, Norway
| | - Timothy Hardcastle
- Dept. of Health - KwaZulu-Natal, Surgery, University of KwaZulu-Natal and Inkosi Albert Luthuli Central Hospital, Durban, South Africa
| | - Deepak Gupta
- All India Institute of Medical Sciences, New Delhi, India
| | - Cino Bendinelli
- Department of Surgery, John Hunter Hospital, Newcastle, Australia
| | - Marco Ceresoli
- General Surgery Dept., Monza University Hospital, Monza, Italy
| | - Vishal G Shelat
- Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore
| | - Richard Ten Broek
- Department of Surgery, Radboud University Medical Center, Njmegen, The Netherlands
| | | | | | - Ibrahima Sall
- Département de Chirurgie, Hôpital Principal de Dakar, Hôpital d'Instruction des Armées, Dakar, Senegal
| | - Mauro Podda
- Department of Surgical Science, University of Cagliari, Cagliari, Italy
| | | | - Igor A Kryvoruchko
- Department of Surgery No. 2, Kharkiv National Medical University, Kharkiv, Ukraine
| | - Philip Stahel
- Department of Surgery, East Carolina University, Brody School of Medicine, Greenville, NC, USA
| | - Kenji Inaba
- LAC+USC Medical Center, Los Angeles, CA, USA
| | - Philippe Montravers
- Département d'Anesthésie-Réanimation CHU Bichat Claude Bernard, Paris, France
| | - Boris Sakakushev
- Research Institute of Medical, University Plovdiv/University Hospital St. George, Plovdiv, Bulgaria
| | - Gabriele Sganga
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Paolo Ballestracci
- General, Emergency and Trauma Surgery Dept., Pisa University Hospital, Via Paradisia, 56124, Pisa, Italy
| | - Manu L N G Malbrain
- First Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, Lublin, Poland
| | | | - Manos Pikoulis
- General Surgery, Hospital, National and Kapodistrian University of Athens (NKUA), Athens, Greece
| | | | - Krstina Doklestic
- Clinic of Emergency Surgery, University Clinical Center of Serbia, Belgrade, Serbia
| | - Massimo Chiarugi
- General, Emergency and Trauma Surgery Dept., Pisa University Hospital, Via Paradisia, 56124, Pisa, Italy
| | - Marco Falcone
- Infectious Disease Dept., Pisa University Hospital, Pisa, Italy
| | - Elena Bignami
- Anesthesiology, Critical Care and Pain Medicine Division, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Viktor Reva
- Department of War Surgery, Kirov Military Medical Academy, Saint-Petersburg, Russia
| | | | - Salomone Di Saverio
- General Surgery Dept, San Benedetto del Tronto Hospital, San Benedetto del Tronto, Italy
| | - Matti Tolonen
- Emergency Surgery, Meilahti Tower Hospital, Helsinki, Finland
| | - Pradeep Navsaria
- Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
| | - Miklosh Bala
- Trauma and Acute Care Surgery Unit, Hadassah - Hebrew University Medical Center, Jerusalem, Israel
| | - Zsolt Balogh
- Department of Traumatology, John Hunter Hospital and University of Newcastle, Newcastle, NSW, Australia
| | - Andrey Litvin
- Department of Surgical Disciplines, Immanuel Kant Baltic Federal University, Regional Clinical Hospital, Kaliningrad, Russia
| | | | - Imtiaz Wani
- Government Gousia Hospital, Srinagar, Kashmir, India
| | | | - Belinda De Simone
- Department of Emergency Surgery, Centre Hospitalier Intercommunal de Villeneuve-Saint-Georges, Villeneuve-Saint-Georges, France
| | - Rao Ivatury
- Virginia Commonwealth University, Richmond, VA, USA
| | | | | | - Edward Tan
- Emergency Department, Radboud University Medical Center, Njmegen, The Netherlands
| | - Chad Ball
- Trauma and Acute Care Surgery, Foothills Medical Center, Calgary, AB, Canada
| | - Carlo Tascini
- Infectious Disease Dept., Udine University Hospital, Udine, Italy
| | - Yunfeng Cui
- Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, China
| | - Raul Coimbra
- Riverside University Health System Medical Center, Riverside, CA, USA
- Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Michael Kelly
- Department of General Surgery, Albury Hospital, Albury, Australia
| | | | | | | | - Nicola De'Angelis
- Service de Chirurgie Digestive et Hépato-Bilio-Pancréatique, Hôpital Henri Mondor, Université Paris Est, Créteil, France
| | - Mircea Chirica
- Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France
| | - Walt L Biffl
- Trauma and Emergency Surgery, Scripss Memorial Hospital, La Jolla, CA, USA
| | - Luca Ansaloni
- General Surgery, Pavia University Hospital, Pavia, Italy
| | - Yoram Kluger
- General Surgery, Rambam Medical Centre, Haifa, Israel
| | - Fausto Catena
- General, Emergency and Trauma Surgery Dept, Bufalini Hospital, Cesena, Italy
| | - Andrew W Kirkpatrick
- General, Acute Care, Abdominal Wall Reconstruction, and Trauma Surgery, Foothills Medical Centre, Calgary, AB, Canada
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Mehrzadi S, Sheibani M, Koosha F, Alinaghian N, Pourhanifeh MH, Tabaeian SAP, Reiter RJ, Hosseinzadeh A. Protective and therapeutic potential of melatonin against intestinal diseases: updated review of current data based on molecular mechanisms. Expert Rev Gastroenterol Hepatol 2023; 17:1011-1029. [PMID: 37796746 DOI: 10.1080/17474124.2023.2267439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 10/03/2023] [Indexed: 10/07/2023]
Abstract
INTRODUCTION Intestinal diseases, a leading global cause of mortality and morbidity, carry a substantial socioeconomic burden. Small and large intestines play pivotal roles in gastrointestinal physiology and food digestion. Pathological conditions, such as gut dysbiosis, inflammation, cancer, therapy-related complications, ulcers, and ischemia, necessitate the urgent exploration of safe and effective complementary therapeutic strategies for optimal intestinal health. AREAS COVERED This article evaluates the potential therapeutic effects of melatonin, a molecule with a wide range of physiological actions, on intestinal diseases including inflammatory bowel disease, irritable bowel syndrome, colon cancer, gastric/duodenal ulcers and other intestinal disorders. EXPERT OPINION Due to anti-inflammatory and antioxidant properties as well as various biological actions, melatonin could be a therapeutic option for improving digestive disorders. However, more researches are needed to fully understand the potential benefits and risks of using melatonin for digestive disorders.
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Affiliation(s)
- Saeed Mehrzadi
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Sheibani
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fereshteh Koosha
- Department of Radiology Technology, Faculty of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nazila Alinaghian
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Russel J Reiter
- Department of Cell Systems and Anatomy, UT Health San Antonio, San Antonio, TX, USA
| | - Azam Hosseinzadeh
- Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
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7
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Kirkpatrick AW, Coccolini F, Tolonen M, Minor S, Catena F, Gois E, Doig CJ, Hill MD, Ansaloni L, Chiarugi M, Tartaglia D, Ioannidis O, Sugrue M, Colak E, Hameed SM, Lampela H, Agnoletti V, McKee JL, Garraway N, Sartelli M, Ball CG, Parry NG, Voght K, Julien L, Kroeker J, Roberts DJ, Faris P, Tiruta C, Moore EE, Ammons LA, Anestiadou E, Bendinelli C, Bouliaris K, Carroll R, Ceresoli M, Favi F, Gurrado A, Rezende-Neto J, Isik A, Cremonini C, Strambi S, Koukoulis G, Testini M, Trpcic S, Pasculli A, Picariello E, Abu-Zidan F, Adeyeye A, Augustin G, Alconchel F, Altinel Y, Hernandez Amin LA, Aranda-Narváez JM, Baraket O, Biffl WL, Baiocchi GL, Bonavina L, Brisinda G, Cardinali L, Celotti A, Chaouch M, Chiarello M, Costa G, de'Angelis N, De Manzini N, Delibegovic S, Di Saverio S, De Simone B, Dubuisson V, Fransvea P, Garulli G, Giordano A, Gomes C, Hayati F, Huang J, Ibrahim AF, Huei TJ, Jailani RF, Khan M, Luna AP, Malbrain MLNG, Marwah S, McBeth P, Mihailescu A, Morello A, Mulita F, Murzi V, Mohammad AT, Parmar S, Pak A, Wong MPK, Pantalone D, Podda M, Puccioni C, Rasa K, Ren J, Roscio F, Gonzalez-Sanchez A, Sganga G, Scheiterle M, Slavchev M, Smirnov D, Tosi L, Trivedi A, Vega JAG, Waledziak M, Xenaki S, Winter D, Wu X, Zakaria AD, Zakaria Z. The unrestricted global effort to complete the COOL trial. World J Emerg Surg 2023; 18:33. [PMID: 37170123 DOI: 10.1186/s13017-023-00500-z.pmid:] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/13/2023] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. A further therapeutic option may be open abdomen (OA) management with negative peritoneal pressure therapy (NPPT) to remove inflammatory ascites and attenuate the systemic damage from SCIAS, although there are definite risks of leaving the abdomen open whenever it might possibly be closed. This potential therapeutic paradigm is the rationale being assessed in the Closed Or Open after Laparotomy (COOL trial) ( https://clinicaltrials.gov/ct2/show/NCT03163095 ). Initially, the COOL trial received Industry sponsorship; however, this funding mandated the use of a specific trademarked and expensive NPPT device in half of the patients allocated to the intervention (open) arm. In August 2022, the 3 M/Acelity Corporation without consultation but within the terms of the contract canceled the financial support of the trial. Although creating financial difficulty, there is now no restriction on specific NPPT devices and removing a cost-prohibitive intervention creates an opportunity to expand the COOL trial to a truly global basis. This document describes the evolution of the COOL trial, with a focus on future opportunities for global growth of the study. METHODS The COOL trial is the largest prospective randomized controlled trial examining the random allocation of SCIAS patients intra-operatively to either formal closure of the fascia or the use of the OA with an application of an NPPT dressing. Patients are eligible if they have free uncontained intraperitoneal contamination and physiologic derangements exemplified by septic shock OR severely adverse predicted clinical outcomes. The primary outcome is intended to definitively inform global practice by conclusively evaluating 90-day survival. Initial recruitment has been lower than hoped but satisfactory, and the COOL steering committee and trial investigators intend with increased global support to continue enrollment until recruitment ensures a definitive answer. DISCUSSION OA is mandated in many cases of SCIAS such as the risk of abdominal compartment syndrome associated with closure, or a planned second look as for example part of "damage control"; however, improved source control (locally and systemically) is the most uncertain indication for an OA. The COOL trial seeks to expand potential sites and proceed with the evaluation of NPPT agnostic to device, to properly examine the hypothesis that this treatment attenuates systemic damage and improves survival. This approach will not affect internal validity and should improve the external validity of any observed results of the intervention. TRIAL REGISTRATION National Institutes of Health ( https://clinicaltrials.gov/ct2/show/NCT03163095 ).
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Affiliation(s)
- Andrew W Kirkpatrick
- Departments of Surgery and Critical Care Medicine, University of Calgary, Foothills Medical Centre, Calgary, AB, EG23T2N 2T9, Canada.
| | - Federico Coccolini
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Pisa, Italy
| | - Matti Tolonen
- Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Samuel Minor
- Departments of Critical Care Medicine and Surgery, Dalhousie University, Halifax, NS, Canada
| | - Fausto Catena
- Department of Surgery, Bufalini Hospital, Cesena, Italy
| | - Emanuel Gois
- Department of Surgery, Londrina State University, and National COOL Coordinator for Brazil, Londrina, Brazil
| | - Christopher J Doig
- Departments of Critical Care Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Michael D Hill
- Department of Clinical Neuroscience and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary and Foothills Medical Centre, Calgary, AB, Canada
| | - Luca Ansaloni
- General Surgery I, San Matteo Hospital Pavia, University of Pavia, Pavia, Italy
| | - Massimo Chiarugi
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Dario Tartaglia
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Orestis Ioannidis
- 4th Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital "George Papanikolaou", Thessaloniki, Greece
| | | | - Elif Colak
- University of Samsun, Samsun Training and Research Hospital, Samsun, Turkey
| | - S Morad Hameed
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Hanna Lampela
- Department of Gastroenterological Surgery, Helsinki University Hospital and University of Helsinki, Espoo, Finland
| | | | - Jessica L McKee
- Global Project Manager, COOL Trial and the TeleMentored Ultrasound Supported Medical Interventions Research Group, Calgary, AB, Canada
| | - Naisan Garraway
- Departments of Surgery and Critical Care Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Massimo Sartelli
- Department of Surgery, Macerata Hospital, Global Alliance for Infections in Surgery, Macerata, Italy
| | - Chad G Ball
- Trauma and Acute Care Surgery, Foothills Medical Center, Calgary, AB, Canada
| | - Neil G Parry
- Departments of Surgery and Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Kelly Voght
- Departments of Surgery and Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Lisa Julien
- Department of Surgery, NSHA-Queen Elizabeth II Health Sciences Center, Dalhousie University, Halifax, NS, Canada
| | - Jenna Kroeker
- Departments of Surgery and Critical Care Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Derek J Roberts
- Division of Vascular and Endovascular Surgery, Department of Surgery and School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | | | | | - Ernest E Moore
- Ernest E. Moore Shock Trauma Center, University of Colorado, Denver, CO, USA
| | | | - Elissavet Anestiadou
- 4th Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital "George Papanikolaou", Thessaloniki, Greece
| | | | - Konstantinos Bouliaris
- General Surgery Department of Koutlimbaneio, Triantafylleio General Hospital of Larissa, Larissa, Thessaly, Greece
| | | | - Marco Ceresoli
- General and Emergency Surgery, School of Medicine and Surgery, Milano-Bicocca University, Monza, Italy
| | - Francesco Favi
- Chirurgia Generale E d'Urgenza, Ospedale M. Bufalini - Cesena, AUSL Della Romagna, Cesena, Italy
| | - Angela Gurrado
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Academic General Surgery "V. Bonomo", University of Bari "A. Moro", Bari, Italy
| | - Joao Rezende-Neto
- Trauma and Acute Care Surgery, General Surgery, St. Michael's Hospital, Toronto, ON, Canada
| | - Arda Isik
- General Surgery Department, Istanbul Medeniyet University School of Medicine Istanbul, Istanbul, Turkey
| | - Camilla Cremonini
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Silivia Strambi
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Georgios Koukoulis
- General Surgery Department of Koutlimbaneio, Triantafylleio General Hospital of Larissa, Larissa, Thessaly, Greece
| | - Mario Testini
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Academic General Surgery "V. Bonomo", University of Bari "A. Moro", Bari, Italy
| | - Sandy Trpcic
- Trauma and Acute Care Surgery, General Surgery, St. Michael's Hospital, Toronto, ON, Canada
| | - Alessandro Pasculli
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Academic General Surgery "V. Bonomo", University of Bari "A. Moro", Bari, Italy
| | - Erika Picariello
- General Surgery Unit, Ospedale M. Buffalini Di Cesena, Cesena, Italy
| | - Fikri Abu-Zidan
- College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Ademola Adeyeye
- Division of Surgical Oncology, Afe Babalola University Multisystem Hospital, Ado-Ekiti, Nigeria
| | - Goran Augustin
- University Hospital Centre Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia
| | - Felipe Alconchel
- Virgen de la Arrixaca University Hospital IMIB-Arrixaca, Ctra. Madrid-Cartagena, S/N, Murcia, Spain
| | - Yuksel Altinel
- Bagcilar Research and Training Hospital, Istanbul, Turkey
| | - Luz Adriana Hernandez Amin
- Nurse Master of Nursing, Professor and Coordinator of the teaching-service relationship, Faculty of Health Sciences, University of Sucre, Sincelejo, Colombia
| | - José Manuel Aranda-Narváez
- Trauma and Emergency Surgery Unit. General, Digestive and Transplantation Surgery Department, University Regional Hospital of Málaga, Malaga, Spain
| | | | | | - Gian Luca Baiocchi
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Luigi Bonavina
- Department of Surgery, University of Milan Medical School, Milan, Italy
| | - Giuseppe Brisinda
- Department of Surgery, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy
| | - Luca Cardinali
- Department of Surgery, General Hospital Madonna del Soccorso, San Benedetto del Tronto, Italy
| | - Andrea Celotti
- General Surgery Unit, UO Chirurgia Generale - Ospedale Maggiore Di Cremona, Cremona, Italy
| | - Mohamed Chaouch
- Department of Visceral and Digestive Surgery, Monastir University, Monastir, Tunisia
| | - Maria Chiarello
- Department of Surgery, Azienda Sanitaria Provinciale Di Cosenza, Cosenza, Italy
| | - Gianluca Costa
- Fondazione Policlinico Campus Bio-Medico, University Campus Bio-Medico of Rome, Rome, Italy
| | - Nicola de'Angelis
- Colorectal and Digestive Surgery Unit-DIGEST Department, Beaujon University Hospital AP-HP, University Paris Cité, Clichy, France
| | - Nicolo De Manzini
- Department of General Surgery, Cattinara University Hospital, Trieste, Italy
| | - Samir Delibegovic
- Department of Proctology, Clinic for Surgery, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina
| | - Salomone Di Saverio
- Department of General Surgery, University of Insubria, University Hospital of Varese, ASST Sette Laghi, Regione Lombardia, Italy
| | - Belinda De Simone
- Unit of Digestive and Metabolic Minimally Invasive Surgery, Clinique Saint Louis, Poissy, Poissy, Ile de France, France
- Unit of Emergency and General Surgery, Guastalla Hospital, AUSL Reggio Emilia, Guastalla, Italy
| | - Vincent Dubuisson
- Chirurgie Digestive, Service de Chirurgie Vasculaire Et, Générale University Hospital of Bordeaux FR, Bordeaux, France
| | | | | | - Alessio Giordano
- Emergency and General Consultant Surgeon, Nuovo Ospedale "S. Stefano", Azienda ASL Toscana Centro, Prato, Italy
| | - Carlos Gomes
- Surgery Unit, Hospital Universitário Terezinha de Jesus, SUPREMA, Juiz de Fora, Brazil
| | - Firdaus Hayati
- Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
| | - Jinjian Huang
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | | | | | | | - Mansoor Khan
- General Surgery, University Hospitals, Sussex, UK
| | | | - Manu L N G Malbrain
- First Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, Lublin, Poland
- International Fluid Academy, Lovenjoel, Belgium
| | - Sanjay Marwah
- Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India
| | | | | | - Alessia Morello
- Department of General Surgery, Madonna del Soccorso Hospital - San Benedetto del Tronto, Italy, Italy
| | - Francesk Mulita
- Department of Surgery, General University Hospital of Patras, Rio, Greece
| | - Valentina Murzi
- Department of Surgical Science, Cagliari State University, Cagliari, Italy
| | | | | | - Ajay Pak
- Department of General Surgery, King George's Medical University, Lucknow, UP, India
| | - Michael Pak-Kai Wong
- School of Medical Sciences & Hospital, Universiti Sains Malaysia, Kelantan, Malaysia
| | | | - Mauro Podda
- Department of Emergency Surgery, Cagliari University Hospital, Cagliari, Italy
| | - Caterina Puccioni
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy
| | - Kemal Rasa
- Department of General Surgery, Hüseyin Kemal Raşa, Anadolu Medical Center, Kocaeli, Turkey
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Francesco Roscio
- Division of General and Minimally Invasive Surgery, ASST Valle Olona, Busto Arsizio, Italy
| | - Antonio Gonzalez-Sanchez
- Trauma and Emergency Surgery Unit. General, Digestive and Transplantation Surgery Department, University Regional Hospital of Málaga, Malaga, Spain
| | - Gabriele Sganga
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy
| | - Maximilian Scheiterle
- Emergency Surgery Unit and Trauma Team, Careggi University Hospital, Florence, Italy
| | | | - Dmitry Smirnov
- Department of Surgery, South Ural State Medical University, Chelyabinsk City, Russia
| | - Lorenzo Tosi
- Department of General Surgery, University of Bologna, Bologna, Italy
| | | | | | | | - Sofia Xenaki
- Department of General Surgery, University Hospital of Heraklion, Crete, Greece
| | | | - Xiuwen Wu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Andee Dzulkarnean Zakaria
- Department of Surgery, School of Medical Sciences and Hospital USM, Universiti Sains Malaysia, Georgetown, Malaysia
| | - Zaidi Zakaria
- Department of Surgery, School of Medical Sciences and Hospital USM, Universiti Sains Malaysia, Georgetown, Malaysia
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8
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Kirkpatrick AW, Coccolini F, Tolonen M, Minor S, Catena F, Gois E, Doig CJ, Hill MD, Ansaloni L, Chiarugi M, Tartaglia D, Ioannidis O, Sugrue M, Colak E, Hameed SM, Lampela H, Agnoletti V, McKee JL, Garraway N, Sartelli M, Ball CG, Parry NG, Voght K, Julien L, Kroeker J, Roberts DJ, Faris P, Tiruta C, Moore EE, Ammons LA, Anestiadou E, Bendinelli C, Bouliaris K, Carroll R, Ceresoli M, Favi F, Gurrado A, Rezende-Neto J, Isik A, Cremonini C, Strambi S, Koukoulis G, Testini M, Trpcic S, Pasculli A, Picariello E, Abu-Zidan F, Adeyeye A, Augustin G, Alconchel F, Altinel Y, Hernandez Amin LA, Aranda-Narváez JM, Baraket O, Biffl WL, Baiocchi GL, Bonavina L, Brisinda G, Cardinali L, Celotti A, Chaouch M, Chiarello M, Costa G, de'Angelis N, De Manzini N, Delibegovic S, Di Saverio S, De Simone B, Dubuisson V, Fransvea P, Garulli G, Giordano A, Gomes C, Hayati F, Huang J, Ibrahim AF, Huei TJ, Jailani RF, Khan M, Luna AP, Malbrain MLNG, Marwah S, McBeth P, Mihailescu A, Morello A, Mulita F, Murzi V, Mohammad AT, Parmar S, Pak A, Wong MPK, Pantalone D, Podda M, Puccioni C, Rasa K, Ren J, Roscio F, Gonzalez-Sanchez A, Sganga G, Scheiterle M, Slavchev M, Smirnov D, Tosi L, Trivedi A, Vega JAG, Waledziak M, Xenaki S, Winter D, Wu X, Zakaria AD, Zakaria Z. The unrestricted global effort to complete the COOL trial. World J Emerg Surg 2023; 18:33. [PMID: 37170123 PMCID: PMC10173926 DOI: 10.1186/s13017-023-00500-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/13/2023] [Indexed: 05/13/2023] Open
Abstract
BACKGROUND Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. A further therapeutic option may be open abdomen (OA) management with negative peritoneal pressure therapy (NPPT) to remove inflammatory ascites and attenuate the systemic damage from SCIAS, although there are definite risks of leaving the abdomen open whenever it might possibly be closed. This potential therapeutic paradigm is the rationale being assessed in the Closed Or Open after Laparotomy (COOL trial) ( https://clinicaltrials.gov/ct2/show/NCT03163095 ). Initially, the COOL trial received Industry sponsorship; however, this funding mandated the use of a specific trademarked and expensive NPPT device in half of the patients allocated to the intervention (open) arm. In August 2022, the 3 M/Acelity Corporation without consultation but within the terms of the contract canceled the financial support of the trial. Although creating financial difficulty, there is now no restriction on specific NPPT devices and removing a cost-prohibitive intervention creates an opportunity to expand the COOL trial to a truly global basis. This document describes the evolution of the COOL trial, with a focus on future opportunities for global growth of the study. METHODS The COOL trial is the largest prospective randomized controlled trial examining the random allocation of SCIAS patients intra-operatively to either formal closure of the fascia or the use of the OA with an application of an NPPT dressing. Patients are eligible if they have free uncontained intraperitoneal contamination and physiologic derangements exemplified by septic shock OR severely adverse predicted clinical outcomes. The primary outcome is intended to definitively inform global practice by conclusively evaluating 90-day survival. Initial recruitment has been lower than hoped but satisfactory, and the COOL steering committee and trial investigators intend with increased global support to continue enrollment until recruitment ensures a definitive answer. DISCUSSION OA is mandated in many cases of SCIAS such as the risk of abdominal compartment syndrome associated with closure, or a planned second look as for example part of "damage control"; however, improved source control (locally and systemically) is the most uncertain indication for an OA. The COOL trial seeks to expand potential sites and proceed with the evaluation of NPPT agnostic to device, to properly examine the hypothesis that this treatment attenuates systemic damage and improves survival. This approach will not affect internal validity and should improve the external validity of any observed results of the intervention. TRIAL REGISTRATION National Institutes of Health ( https://clinicaltrials.gov/ct2/show/NCT03163095 ).
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Affiliation(s)
- Andrew W Kirkpatrick
- Departments of Surgery and Critical Care Medicine, University of Calgary, Foothills Medical Centre, Calgary, AB, EG23T2N 2T9, Canada.
| | - Federico Coccolini
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Pisa, Italy
| | - Matti Tolonen
- Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Samuel Minor
- Departments of Critical Care Medicine and Surgery, Dalhousie University, Halifax, NS, Canada
| | - Fausto Catena
- Department of Surgery, Bufalini Hospital, Cesena, Italy
| | - Emanuel Gois
- Department of Surgery, Londrina State University, and National COOL Coordinator for Brazil, Londrina, Brazil
| | - Christopher J Doig
- Departments of Critical Care Medicine and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Michael D Hill
- Department of Clinical Neuroscience and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary and Foothills Medical Centre, Calgary, AB, Canada
| | - Luca Ansaloni
- General Surgery I, San Matteo Hospital Pavia, University of Pavia, Pavia, Italy
| | - Massimo Chiarugi
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Dario Tartaglia
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Orestis Ioannidis
- 4th Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital "George Papanikolaou", Thessaloniki, Greece
| | | | - Elif Colak
- University of Samsun, Samsun Training and Research Hospital, Samsun, Turkey
| | - S Morad Hameed
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| | - Hanna Lampela
- Department of Gastroenterological Surgery, Helsinki University Hospital and University of Helsinki, Espoo, Finland
| | | | - Jessica L McKee
- Global Project Manager, COOL Trial and the TeleMentored Ultrasound Supported Medical Interventions Research Group, Calgary, AB, Canada
| | - Naisan Garraway
- Departments of Surgery and Critical Care Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Massimo Sartelli
- Department of Surgery, Macerata Hospital, Global Alliance for Infections in Surgery, Macerata, Italy
| | - Chad G Ball
- Trauma and Acute Care Surgery, Foothills Medical Center, Calgary, AB, Canada
| | - Neil G Parry
- Departments of Surgery and Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Kelly Voght
- Departments of Surgery and Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Lisa Julien
- Department of Surgery, NSHA-Queen Elizabeth II Health Sciences Center, Dalhousie University, Halifax, NS, Canada
| | - Jenna Kroeker
- Departments of Surgery and Critical Care Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Derek J Roberts
- Division of Vascular and Endovascular Surgery, Department of Surgery and School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | | | | | - Ernest E Moore
- Ernest E. Moore Shock Trauma Center, University of Colorado, Denver, CO, USA
| | | | - Elissavet Anestiadou
- 4th Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital "George Papanikolaou", Thessaloniki, Greece
| | | | - Konstantinos Bouliaris
- General Surgery Department of Koutlimbaneio, Triantafylleio General Hospital of Larissa, Larissa, Thessaly, Greece
| | | | - Marco Ceresoli
- General and Emergency Surgery, School of Medicine and Surgery, Milano-Bicocca University, Monza, Italy
| | - Francesco Favi
- Chirurgia Generale E d'Urgenza, Ospedale M. Bufalini - Cesena, AUSL Della Romagna, Cesena, Italy
| | - Angela Gurrado
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Academic General Surgery "V. Bonomo", University of Bari "A. Moro", Bari, Italy
| | - Joao Rezende-Neto
- Trauma and Acute Care Surgery, General Surgery, St. Michael's Hospital, Toronto, ON, Canada
| | - Arda Isik
- General Surgery Department, Istanbul Medeniyet University School of Medicine Istanbul, Istanbul, Turkey
| | - Camilla Cremonini
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Silivia Strambi
- Emergency Surgery and Trauma Center, University of Pisa, Pisa, Italy
| | - Georgios Koukoulis
- General Surgery Department of Koutlimbaneio, Triantafylleio General Hospital of Larissa, Larissa, Thessaly, Greece
| | - Mario Testini
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Academic General Surgery "V. Bonomo", University of Bari "A. Moro", Bari, Italy
| | - Sandy Trpcic
- Trauma and Acute Care Surgery, General Surgery, St. Michael's Hospital, Toronto, ON, Canada
| | - Alessandro Pasculli
- Department of Precision and Regenerative Medicine and Ionian Area, Unit of Academic General Surgery "V. Bonomo", University of Bari "A. Moro", Bari, Italy
| | - Erika Picariello
- General Surgery Unit, Ospedale M. Buffalini Di Cesena, Cesena, Italy
| | - Fikri Abu-Zidan
- College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates
| | - Ademola Adeyeye
- Division of Surgical Oncology, Afe Babalola University Multisystem Hospital, Ado-Ekiti, Nigeria
| | - Goran Augustin
- University Hospital Centre Zagreb, School of Medicine University of Zagreb, Zagreb, Croatia
| | - Felipe Alconchel
- Virgen de la Arrixaca University Hospital IMIB-Arrixaca, Ctra. Madrid-Cartagena, S/N, Murcia, Spain
| | - Yuksel Altinel
- Bagcilar Research and Training Hospital, Istanbul, Turkey
| | - Luz Adriana Hernandez Amin
- Nurse Master of Nursing, Professor and Coordinator of the teaching-service relationship, Faculty of Health Sciences, University of Sucre, Sincelejo, Colombia
| | - José Manuel Aranda-Narváez
- Trauma and Emergency Surgery Unit. General, Digestive and Transplantation Surgery Department, University Regional Hospital of Málaga, Malaga, Spain
| | | | | | - Gian Luca Baiocchi
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Luigi Bonavina
- Department of Surgery, University of Milan Medical School, Milan, Italy
| | - Giuseppe Brisinda
- Department of Surgery, Fondazione Policlinico Universitario A Gemelli IRCCS, Rome, Italy
| | - Luca Cardinali
- Department of Surgery, General Hospital Madonna del Soccorso, San Benedetto del Tronto, Italy
| | - Andrea Celotti
- General Surgery Unit, UO Chirurgia Generale - Ospedale Maggiore Di Cremona, Cremona, Italy
| | - Mohamed Chaouch
- Department of Visceral and Digestive Surgery, Monastir University, Monastir, Tunisia
| | - Maria Chiarello
- Department of Surgery, Azienda Sanitaria Provinciale Di Cosenza, Cosenza, Italy
| | - Gianluca Costa
- Fondazione Policlinico Campus Bio-Medico, University Campus Bio-Medico of Rome, Rome, Italy
| | - Nicola de'Angelis
- Colorectal and Digestive Surgery Unit-DIGEST Department, Beaujon University Hospital AP-HP, University Paris Cité, Clichy, France
| | - Nicolo De Manzini
- Department of General Surgery, Cattinara University Hospital, Trieste, Italy
| | - Samir Delibegovic
- Department of Proctology, Clinic for Surgery, University Clinical Center Tuzla, Tuzla, Bosnia and Herzegovina
| | - Salomone Di Saverio
- Department of General Surgery, University of Insubria, University Hospital of Varese, ASST Sette Laghi, Regione Lombardia, Italy
| | - Belinda De Simone
- Unit of Digestive and Metabolic Minimally Invasive Surgery, Clinique Saint Louis, Poissy, Poissy, Ile de France, France
- Unit of Emergency and General Surgery, Guastalla Hospital, AUSL Reggio Emilia, Guastalla, Italy
| | - Vincent Dubuisson
- Chirurgie Digestive, Service de Chirurgie Vasculaire Et, Générale University Hospital of Bordeaux FR, Bordeaux, France
| | | | | | - Alessio Giordano
- Emergency and General Consultant Surgeon, Nuovo Ospedale "S. Stefano", Azienda ASL Toscana Centro, Prato, Italy
| | - Carlos Gomes
- Surgery Unit, Hospital Universitário Terezinha de Jesus, SUPREMA, Juiz de Fora, Brazil
| | - Firdaus Hayati
- Department of Surgery, Faculty of Medicine and Health Sciences, Universiti Malaysia Sabah, Kota Kinabalu, Sabah, Malaysia
| | - Jinjian Huang
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | | | | | | | - Mansoor Khan
- General Surgery, University Hospitals, Sussex, UK
| | | | - Manu L N G Malbrain
- First Department of Anaesthesiology and Intensive Therapy, Medical University of Lublin, Lublin, Poland
- International Fluid Academy, Lovenjoel, Belgium
| | - Sanjay Marwah
- Postgraduate Institute of Medical Sciences, Rohtak, Haryana, India
| | | | | | - Alessia Morello
- Department of General Surgery, Madonna del Soccorso Hospital - San Benedetto del Tronto, Italy, Italy
| | - Francesk Mulita
- Department of Surgery, General University Hospital of Patras, Rio, Greece
| | - Valentina Murzi
- Department of Surgical Science, Cagliari State University, Cagliari, Italy
| | | | | | - Ajay Pak
- Department of General Surgery, King George's Medical University, Lucknow, UP, India
| | - Michael Pak-Kai Wong
- School of Medical Sciences & Hospital, Universiti Sains Malaysia, Kelantan, Malaysia
| | | | - Mauro Podda
- Department of Emergency Surgery, Cagliari University Hospital, Cagliari, Italy
| | - Caterina Puccioni
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy
| | - Kemal Rasa
- Department of General Surgery, Hüseyin Kemal Raşa, Anadolu Medical Center, Kocaeli, Turkey
| | - Jianan Ren
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Francesco Roscio
- Division of General and Minimally Invasive Surgery, ASST Valle Olona, Busto Arsizio, Italy
| | - Antonio Gonzalez-Sanchez
- Trauma and Emergency Surgery Unit. General, Digestive and Transplantation Surgery Department, University Regional Hospital of Málaga, Malaga, Spain
| | - Gabriele Sganga
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of Sacred Heart, Rome, Italy
| | - Maximilian Scheiterle
- Emergency Surgery Unit and Trauma Team, Careggi University Hospital, Florence, Italy
| | | | - Dmitry Smirnov
- Department of Surgery, South Ural State Medical University, Chelyabinsk City, Russia
| | - Lorenzo Tosi
- Department of General Surgery, University of Bologna, Bologna, Italy
| | | | | | | | - Sofia Xenaki
- Department of General Surgery, University Hospital of Heraklion, Crete, Greece
| | | | - Xiuwen Wu
- Research Institute of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China
| | - Andee Dzulkarnean Zakaria
- Department of Surgery, School of Medical Sciences and Hospital USM, Universiti Sains Malaysia, Georgetown, Malaysia
| | - Zaidi Zakaria
- Department of Surgery, School of Medical Sciences and Hospital USM, Universiti Sains Malaysia, Georgetown, Malaysia
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9
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Ferrada P, Cannon JW, Kozar RA, Bulger EM, Sugrue M, Napolitano LM, Tisherman SA, Coopersmith CM, Efron PA, Dries DJ, Dunn TB, Kaplan LJ. Surgical Science and the Evolution of Critical Care Medicine. Crit Care Med 2023; 51:182-211. [PMID: 36661448 DOI: 10.1097/ccm.0000000000005708] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Surgical science has driven innovation and inquiry across adult and pediatric disciplines that provide critical care regardless of location. Surgically originated but broadly applicable knowledge has been globally shared within the pages Critical Care Medicine over the last 50 years.
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Affiliation(s)
- Paula Ferrada
- Division of Trauma and Acute Care Surgery, Department of Surgery, Inova Fairfax Hospital, Falls Church, VA
| | - Jeremy W Cannon
- Division of Trauma, Surgical Critical Care and Emergency Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Rosemary A Kozar
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Eileen M Bulger
- Division of Trauma, Burn and Critical Care Surgery, Department of Surgery, University of Washington at Seattle, Harborview, Seattle, WA
| | - Michael Sugrue
- Department of Surgery, Letterkenny University Hospital, County of Donegal, Ireland
| | - Lena M Napolitano
- Division of Acute Care Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI
| | - Samuel A Tisherman
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Craig M Coopersmith
- Division of General Surgery, Department of Surgery, Emory University, Emory Critical Care Center, Atlanta, GA
| | - Phil A Efron
- Department of Surgery, Division of Critical Care, University of Florida, Gainesville, FL
| | - David J Dries
- Department of Surgery, University of Minnesota, Regions Healthcare, St. Paul, MN
| | - Ty B Dunn
- Division of Transplant Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Lewis J Kaplan
- Division of Trauma, Surgical Critical Care and Emergency Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Corporal Michael J. Crescenz VA Medical Center, Section of Surgical Critical Care, Surgical Services, Philadelphia, PA
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10
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Voth M, Verboket R, Henrich D, Marzi I. L-FABP and NGAL are novel biomarkers for detection of abdominal injury and hemorrhagic shock. Injury 2023; 54:1246-1256. [PMID: 36621362 DOI: 10.1016/j.injury.2023.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/15/2022] [Accepted: 01/01/2023] [Indexed: 01/04/2023]
Abstract
INTRODUCTION Delayed diagnosis of abdominal injuries and hemorrhagic shock leads to secondary complications and high late mortality in severely traumatized patients. The liver fatty acid-binding protein (L-FABP) is expressed in intestine, liver and kidney; the neutrophil gelatinase-associated lipocalin (NGAL) in colon and kidney. We hypothesized that l-FABP is an early biomarker for abdominal injury and hemorrhagic shock and that l-FABP and NGAL are specific markers for detection of liver and/or kidney injuries. PATIENTS AND METHODS Traumatized patients with an age ≥18 years and an abdominal injury (AISabd≥2), independently from Injury Severity Score (ISS), were prospectively included from 04/2018 to 05/2021. 68 patients had an abdominal injury ("Abd") and 10 patients had an abdominal injury with hemorrhagic shock ("HS Abd"). 41 patients without abdominal injury and hemorrhagic shock but with an ISS ≥ 25 ("noAbd") were included as control group. Four abdominal subgroups with isolated organ injuries were defined. Plasma l-FABP and NGAL levels were measured at admission (ER) and up to two days post-trauma. RESULTS All patient groups had a median ISS≥25. In ER, median l-FABP levels were significantly higher in "HS Abd" group (1209.2 ng/ml [IQR=575.2-1780.3]) compared to "noAbd" group (36.4 ng/ml [IQR=14.8-88.5]), and to "Abd" group (41.4 ng/ml [IQR=18.0-235.5]), p<0.001. In matched-pair-analysis l-FABP levels in the group "Abd" were significantly higher (108.3 ng/ml [IQR=31.4-540.9]) compared to "noAbd" (26.4 ng/ml [IQR=15.5-88.8]), p = 0.0016. l-FABP correlated significantly with clinical parameters of hemorrhagic shock; the optimal cut-off level of l-FABP for detection was 334.3 ng/ml (sensitivity: 90%, specificity: 78%). Median l-FABP-levels were significantly higher in patients with isolated liver or kidney injuries and correlated significantly with AST, ALT and creatinine value. Median NGAL levels in the ER were significantly higher in "HS Abd" group (115.9 ng/ml [IQR=90.6-163.8]) compared to "noAbd" group (58.5 ng/ml [IQR=41.0-89.6],p<0.001) and "Abd" group (70.5 ng/ml [IQR=53.3-115.5], p<0.05). The group "Abd" showed significant higher median NGAL levels compared to "noAbd", p = 0.019. NGAL levels correlated significantly with clinical parameters of hemorrhagic shock. CONCLUSION L-FABP and NGAL are novel biomarkers for detection of abdominal trauma and hemorrhagic shock. l-FABP may be a useful and promising parameter in diagnosis of liver and kidney injuries, NGAL failed to achieve the same.
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Affiliation(s)
- M Voth
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.
| | - R Verboket
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - D Henrich
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - I Marzi
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
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11
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Xu W, Zheng Y, Suo Z, Fei K, Wang Y, Liu C, Li S, Zhang M, Zhang Y, Zheng Z, Ni C, Zheng H. Effect of dexmedetomidine on postoperative systemic inflammation and recovery in patients undergoing digest tract cancer surgery: A meta-analysis of randomized controlled trials. Front Oncol 2022; 12:970557. [PMID: 36185178 PMCID: PMC9518820 DOI: 10.3389/fonc.2022.970557] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/29/2022] [Indexed: 01/30/2023] Open
Abstract
Perioperative immune function, postoperative cognitive function and prognosis are momentous issues for patients undergoing digestive tract cancer surgery. Studies have investigated the efficacy of dexmedetomidine (DEX) administration on these issues, but the results are inconsistent. Therefore, this meta-analysis aimed to summarize all the existing evidence and draw a conclusion more accurately on these associations. Trials were located through electronic searches of the PubMed, Embase, the Cochrane Library and Web of Science databases sources (from the establishment date of databases to April 2022). Bibliographies of the retrieved articles were checked. A total of 17 RCTs involving 1619 patients were included. The results showed that DEX decreased the level of C-reactive protein (SMD = -4.26, 95%CI: -6.16, -2.36), TNF-α (SMD = -4.22, 95%CI: -5.91, -2.54) and IL-6 (SMD = -2.71, 95%CI: -4.46, -0.97), and increased the level of IL-10 (SMD = 1.74, 95%CI: 0.25, 3.24). DEX also increased CD4+ T cells (SMD = 0.55, 95%CI: 0.29, 0.82) and CD4+/CD8+ ratio (SMD = 0.62, 95%CI: 0.24, 1.01). Thus, DEX was associated with alleviation of postoperative systemic inflammatory response and immune dysfunction. Furthermore, DEX increased mini-mental state examination scores at 12h (SMD = 1.10, 95%CI: 0.74,1.45), 24h (SMD = 0.85, 95%CI: 0.59, 1.11), 48h (SMD = 0.89, 95%CI: 0.50, 1.28) and 72h (SMD = 0.75, 95%CI: 0.38, 1.11) after surgery. DEX decreased the occurrence of postoperative cognitive dysfunction (POCD) at 24h (OR = 0.22, 95%CI: 0.11, 0.46) and 72h (OR = 0.39, 95%CI: 0.22, 0.68) after surgery. DEX decreased first flatus time (SMD = -1.55, 95%CI: -2.82, -0.27) and hospital stay (SMD = -1.23, 95%CI: -1.88, -0.59). Therefore, based on perioperative immune dysfunction alleviation, DEX attenuated POCD and potential neuroinflammation, improved postoperative recovery and clinical prognosis of patients undergoing digest tract cancer surgery. Further studies are necessary to elucidate the clinical application of DEX from an immunological perspective.
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Affiliation(s)
- Wenjie Xu
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuxiang Zheng
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zizheng Suo
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kailun Fei
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yalong Wang
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chao Liu
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shuai Li
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingzhu Zhang
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yefan Zhang
- Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhaoxu Zheng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cheng Ni
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- *Correspondence: Cheng Ni,
| | - Hui Zheng
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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12
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Martel J, Chang SH, Ko YF, Hwang TL, Young JD, Ojcius DM. Gut barrier disruption and chronic disease. Trends Endocrinol Metab 2022; 33:247-265. [PMID: 35151560 DOI: 10.1016/j.tem.2022.01.002] [Citation(s) in RCA: 236] [Impact Index Per Article: 78.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 01/03/2022] [Accepted: 01/10/2022] [Indexed: 02/06/2023]
Abstract
The intestinal barrier protects the host against gut microbes, food antigens, and toxins present in the gastrointestinal tract. However, gut barrier integrity can be affected by intrinsic and extrinsic factors, including genetic predisposition, the Western diet, antibiotics, alcohol, circadian rhythm disruption, psychological stress, and aging. Chronic disruption of the gut barrier can lead to translocation of microbial components into the body, producing systemic, low-grade inflammation. While the association between gut barrier integrity and inflammation in intestinal diseases is well established, we review here recent studies indicating that the gut barrier and microbiota dysbiosis may contribute to the development of metabolic, autoimmune, and aging-related disorders. Emerging interventions to improve gut barrier integrity and microbiota composition are also described.
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Affiliation(s)
- Jan Martel
- Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Shih-Hsin Chang
- Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan
| | - Yun-Fei Ko
- Chang Gung Immunology Consortium, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Chang Gung Biotechnology Corporation, Taipei, Taiwan; Biochemical Engineering Research Center, Ming Chi University of Technology, New Taipei City, Taiwan
| | - Tsong-Long Hwang
- Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - John D Young
- Chang Gung Biotechnology Corporation, Taipei, Taiwan.
| | - David M Ojcius
- Center for Molecular and Clinical Immunology, Chang Gung University, Taoyuan, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Biomedical Sciences, Arthur Dugoni School of Dentistry, University of the Pacific, San Francisco, CA, USA.
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13
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Stanculescu D, Bergquist J. Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Med (Lausanne) 2022; 9:818728. [PMID: 35345768 PMCID: PMC8957276 DOI: 10.3389/fmed.2022.818728] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/11/2022] [Indexed: 12/15/2022] Open
Abstract
We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical illness research. Specifically, we combine emerging findings regarding (a) hypoperfusion and endotheliopathy, and (b) intestinal injury in these illnesses with our previously published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid hormone function associated with redox imbalance in ME/CFS. Moreover, we describe interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This paper summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS. New knowledge on diagnostics, prognostics and treatment strategies could be gained through active collaboration between critical illness and ME/CFS researchers, which could lead to improved outcomes for both conditions.
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Affiliation(s)
| | - Jonas Bergquist
- Division of Analytical Chemistry and Neurochemistry, Department of Chemistry - Biomedical Center, Uppsala University, Uppsala, Sweden.,The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Collaborative Research Centre at Uppsala University, Uppsala, Sweden
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14
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Micronutrient Improvement of Epithelial Barrier Function in Various Disease States: A Case for Adjuvant Therapy. Int J Mol Sci 2022; 23:ijms23062995. [PMID: 35328419 PMCID: PMC8951934 DOI: 10.3390/ijms23062995] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 03/01/2022] [Indexed: 02/04/2023] Open
Abstract
The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care—but also medical prophylactic and therapeutic care in general—to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.
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15
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The Rationale and Current Status of Endotoxin Adsorption in the Treatment of Septic Shock. J Clin Med 2022; 11:jcm11030619. [PMID: 35160068 PMCID: PMC8836955 DOI: 10.3390/jcm11030619] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 02/05/2023] Open
Abstract
Lipopolysaccharide, the main component of the outer membrane of Gram-negative bacteria is a highly potent endotoxin responsible for organ dysfunction in sepsis. It is present in the blood stream not only in Gram-negative infections, but also in Gram-positive and fungal infections, presumably due to sepsis-related disruption of the intestinal barrier. Various pathways, both extra- and intracellular, are involved in sensing endotoxin and non-canonical activation of caspase-mediated pyroptosis is considered to have a major role in sepsis pathophysiology. Endotoxin induces specific pathological alterations in several organs, which contributes to poor outcomes. The adverse consequences of endotoxin in the circulation support the use of anti-endotoxin therapies, yet more than 30 years of experience with endotoxin adsorption therapies have not provided clear evidence in favor of this treatment modality. The results of small studies support timely endotoxin removal guided by measuring the levels of endotoxin; unfortunately, this has not been proven in large, randomized studies. The presence of endotoxemia can be demonstrated in the majority of patients with COVID-19, yet only case reports and case series describing the effects of endotoxin removal in these patients have been published to date. The place of blood purification therapies in the treatment of septic shock has not yet been determined.
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16
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Wang H, Wang H, Sun Y, Ren Z, Zhu W, Li A, Cui G. Potential Associations Between Microbiome and COVID-19. Front Med (Lausanne) 2022; 8:785496. [PMID: 35004750 PMCID: PMC8727742 DOI: 10.3389/fmed.2021.785496] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 11/22/2021] [Indexed: 12/12/2022] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has plunged the world into a major crisis. The disease is characterized by strong infectivity, high morbidity, and high mortality. It is still spreading in some countries. Microbiota and their metabolites affect human physiological health and diseases by participating in host digestion and nutrition, promoting metabolic function, and regulating the immune system. Studies have shown that human microecology is associated with many diseases, including COVID-19. In this research, we first reviewed the microbial characteristics of COVID-19 from the aspects of gut microbiome, lung microbime, and oral microbiome. We found that significant changes take place in both the gut microbiome and airway microbiome in patients with COVID-19 and are characterized by an increase in conditional pathogenic bacteria and a decrease in beneficial bacteria. Then, we summarized the possible microecological mechanisms involved in the progression of COVID-19. Intestinal microecological disorders in individuals may be involved in the occurrence and development of COVID-19 in the host through interaction with ACE2, mitochondria, and the lung-gut axis. In addition, fecal bacteria transplantation (FMT), prebiotics, and probiotics may play a positive role in the treatment of COVID-19 and reduce the fatal consequences of the disease.
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Affiliation(s)
- Huifen Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Zhengzhou, China.,Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Haiyu Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Zhengzhou, China.,Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ying Sun
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Zhengzhou, China.,Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Zhengzhou, China.,Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Weiwei Zhu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Zhengzhou, China.,Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Zhengzhou, China.,Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Guangying Cui
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Gene Hospital of Henan Province, Zhengzhou, China.,Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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17
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Birgin E, Yang C, Brunner A, Hetjens S, Rahbari M, Bork U, Reissfelder C, Weitz J, Rahbari NN. A postresection perfusion deficit in the right colon is an independent predictor of perioperative outcome after major hepatectomy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 29:785-797. [PMID: 34856068 DOI: 10.1002/jhbp.1089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/25/2021] [Accepted: 11/03/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND There is a strong interaction between hepatic hemodynamics and perfusion in the splanchnic system. However, little is known about differences in perfusion in different splanchnic compartments and their changes after hepatectomy. METHODS Perfusion in various splanchnic compartments (ie, stomach, small intestine, right and left colon, liver) was assessed pre- and post-hepatectomy by intraoperative laser Doppler flowmetry. Differences of splanchnic perfusion between compartments were evaluated by ANOVA, and risk factors of postoperative complications (graded by the comprehensive complication index [CCI]) were analyzed by univariate and multivariate analyses. A prediction model of postoperative complications was developed. RESULTS A total of 50 and 29 patients with major and minor hepatectomy were enrolled. Splanchnic perfusion at baseline varied significantly across different splanchnic compartments with highest values in the small bowel and right colon (P < .001). Major hepatectomy induced a significant perfusion decrease in the stomach (P = .006), right colon (P < .001) and small bowel (P = .035). A postresection perfusion deficit in the right colon with values below 254 perfusion units (PU) was identified as an independent predictor of clinically relevant complications after major hepatectomy (concordance index: 0.79, 95% CI 0.66-0.87, P = .002). Bootstrap validation confirmed internal validity and excellent calibration. CONCLUSIONS Major hepatectomy causes significant reduction of splanchnic perfusion. An intraoperative posthepatectomy microcirculatory perfusion deficit of the right colon is a strong and independent predictor of clinically relevant postoperative complications after major hepatectomy.
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Affiliation(s)
- Emrullah Birgin
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Cui Yang
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Anna Brunner
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Svetlana Hetjens
- Department of Medical Statistics and Biomathematics, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Mohammad Rahbari
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Ulrich Bork
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Christoph Reissfelder
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
| | - Jürgen Weitz
- Department of Gastrointestinal, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Nuh N Rahbari
- Department of Surgery, Medical Faculty Mannheim, Universitätsmedizin Mannheim, Heidelberg University, Mannheim, Germany
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18
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Watson MA, Pattavina B, Hilsabeck TAU, Lopez‐Dominguez J, Kapahi P, Brand MD. S3QELs protect against diet-induced intestinal barrier dysfunction. Aging Cell 2021; 20:e13476. [PMID: 34521156 PMCID: PMC8520719 DOI: 10.1111/acel.13476] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/11/2021] [Accepted: 08/27/2021] [Indexed: 12/31/2022] Open
Abstract
The underlying causes of aging remain elusive, but may include decreased intestinal homeostasis followed by disruption of the intestinal barrier, which can be mimicked by nutrient‐rich diets. S3QELs are small‐molecule suppressors of site IIIQo electron leak; they suppress superoxide generation at complex III of the mitochondrial electron transport chain without inhibiting oxidative phosphorylation. Here we show that feeding different S3QELs to Drosophila on a high‐nutrient diet protects against greater intestinal permeability, greater enterocyte apoptotic cell number, and shorter median lifespan. Hif‐1α knockdown in enterocytes also protects, and blunts any further protection by S3QELs. Feeding S3QELs to mice on a high‐fat diet also protects against the diet‐induced increase in intestinal permeability. Our results demonstrate by inference of S3QEL use that superoxide produced by complex III in enterocytes contributes to diet‐induced intestinal barrier disruption in both flies and mice.
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Affiliation(s)
- Mark A. Watson
- The Buck Institute for Research on Aging Novato California USA
| | | | | | | | - Pankaj Kapahi
- The Buck Institute for Research on Aging Novato California USA
| | - Martin D. Brand
- The Buck Institute for Research on Aging Novato California USA
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19
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Ji X, Sheng Y, Guan Y, Li Y, Xu Y, Tang L. Evaluation of Calu-3 cell lines as an in vitro model to study the inhalation toxicity of flavoring extracts. Toxicol Mech Methods 2021; 32:171-179. [PMID: 34488543 DOI: 10.1080/15376516.2021.1977880] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
This study aimed to evaluate the characteristics of Calu-3 cells as a model to examine the toxicological responses of inhalable substances. Calu-3 cells were grown to the confluence at an air-liquid interface (ALI) using a Transwell® permeable support system. The ALI resulted in biomimetic native bronchial epithelium displaying pseudostratified columnar epithelium with more microvilli and secretory vesicles. We further characterized and optimized the Calu-3 cell line model using ALI culturing conditions, immunolabeling of protein expression, ultrastructural analysis using scanning electron microscopy (SEM), and transepithelial electrical resistance (TEER) measurements, and then screened for the cytotoxicity of tobacco flavoring extracts. Calu-3 cells displayed dose-dependent responses when treated with the flavoring extract. Within 8-10 days, cell monolayers developed TEER ≥1000 Ω·cm2. During this time, Calu-3 cells exposed to flavoring extracts X01 and X06 exhibited a loss of cellular integrity and decreased ZO-1 and E-cadherin protein expression. In conclusion, we investigated the Calu-3 cell line culture conditions, culture time, and barrier integrity and tested the effect of six new synthetic tobacco flavoring extracts. Our data demonstrate that the Calu-3 human bronchial epithelial cell monolayer system is a potential in vitro model to assess the inhalation toxicity of inhalable substances.
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Affiliation(s)
- Xiaoli Ji
- Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai, China.,NMPA Key Laboratory for Quality Analysis of Chemical Drug Preparations, Shanghai, China
| | - Yunhua Sheng
- Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai, China.,NMPA Key Laboratory for Quality Analysis of Chemical Drug Preparations, Shanghai, China
| | - Ying Guan
- China Tobacco Yunnan Industrial Co., Ltd., Kunming, China
| | - Yinxia Li
- Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai, China.,School of Pharmacy, Fudan University, Shanghai, China
| | - Yuqiong Xu
- China Tobacco Yunnan Industrial Co., Ltd., Kunming, China
| | - Liming Tang
- Pharmacology and Toxicology Department, Shanghai Institute for Food and Drug Control, Shanghai, China.,NMPA Key Laboratory for Quality Analysis of Chemical Drug Preparations, Shanghai, China
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20
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Royster W, Ochani M, Aziz M, Wang P. Therapeutic Potential of B-1a Cells in Intestinal Ischemia-reperfusion Injury. J Surg Res 2021; 268:326-336. [PMID: 34399355 DOI: 10.1016/j.jss.2021.06.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/14/2021] [Accepted: 06/29/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Acute mesenteric ischemia is a common surgical emergency. Restoration of blood flow is a critical objective of treating this pathology. However, many patients suffer from ischemia-reperfusion (I/R) injuries at the time of revascularization, requiring prolonged hospitalizations. B-1a cells are a subtype of B lymphocytes with roles in regulating inflammation and tissue injury by spontaneous release of natural IgM and IL-10. We hypothesized that treatment with B-1a cells protects mice from intestinal I/R. METHODS Mesenteric ischemia was induced in mice by placing a vascular clip on the superior mesenteric artery for 60 minutes. At the time of reperfusion, B-1a cells or PBS control were instilled into the peritoneal cavity (PerC) of mice. PerC lavage, blood, intestine, and lungs were collected 4 h after reperfusion. Serum organ injury and inflammatory markers such as ALT, AST, LDH, lactate, IL-6, as well as lung and gut histology and myeloperoxidase (MPO) were assessed. RESULTS In intestinal I/R, B-1a cell frequency and number in the PerC were significantly decreased compared to sham-operated mice. There was an increase in the serum levels of ALT, AST, LDH, lactate, and IL-6 when comparing the vehicle group with the sham group. These increases were significantly reduced in the B-1a cell treated group. B-1a cell treatment significantly decreased the intestine and lung injury scores as well as MPO content, compared to vehicle treated mice. B-1a cell treatment resulted in a reduction of apoptotic cells in these tissues. Serum IgM levels were decreased in intestinal I/R, while treatment with B-1a cells significantly increased their levels towards normal levels. CONCLUSIONS B-1a cell treatment at the time of mesenteric reperfusion ameliorates end organ damage and reduces systemic inflammation through the improvement of serum IgM levels. Preserving B-1a cells pool could serve as a novel therapeutic avenue in intestinal I/R injury.
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Affiliation(s)
- William Royster
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York; Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, Manhasset, New York
| | - Mahendar Ochani
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York; Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, Manhasset, New York
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York; Elmezzi Graduate School of Molecular Medicine, Manhasset, New York; Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, Manhasset, New York; Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York.
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21
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Hundscheid IHR, Schellekens DHSM, Grootjans J, Den Dulk M, Van Dam RM, Beets GL, Buurman WA, Lenaerts K, Derikx JPM, Dejong CHC. Evaluating the safety of two human experimental intestinal ischemia reperfusion models: A retrospective observational study. PLoS One 2021; 16:e0253506. [PMID: 34143845 PMCID: PMC8213171 DOI: 10.1371/journal.pone.0253506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 06/05/2021] [Indexed: 11/18/2022] Open
Abstract
Background We developed a jejunal and colonic experimental human ischemia-reperfusion (IR) model to study pathophysiological intestinal IR mechanisms and potential new intestinal ischemia biomarkers. Our objective was to evaluate the safety of these IR models by comparing patients undergoing surgery with and without in vivo intestinal IR. Methods A retrospective study was performed comparing complication rates and severity, based on the Clavien-Dindo classification system, in patients undergoing pancreatoduodenectomy with (n = 10) and without (n = 20 matched controls) jejunal IR or colorectal surgery with (n = 10) and without (n = 20 matched controls) colon IR. Secondary outcome parameters were operative time, blood loss, 90-day mortality and length of hospital stay. Results Following pancreatic surgery, 63% of the patients experienced one or more postoperative complications. There was no significant difference in incidence or severity of complications between patients undergoing pancreatic surgery with (70%) or without (60%, P = 0.7) jejunal IR. Following colorectal surgery, 60% of the patients experienced one or more postoperative complication. Complication rate and severity were similar in patients with (50%) and without (65%, P = 0.46) colonic IR. Operative time, amount of blood loss, postoperative C-reactive protein, length of hospital stay or mortality were equal in both intervention and control groups for jejunal and colon IR. Conclusion This study showed that human experimental intestinal IR models are safe in patients undergoing pancreatic or colorectal surgery.
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Affiliation(s)
- Inca H. R. Hundscheid
- Department of Pathology, Maastricht University Medical Centre+, Maastricht, The Netherlands
- NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
- * E-mail:
| | - Dirk H. S. M. Schellekens
- NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Joep Grootjans
- NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Marcel Den Dulk
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Ronald M. Van Dam
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Surgery, RWTH University Hospital Aachen, Aachen, Germany
| | - Geerard L. Beets
- Department of Surgery, The Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
- GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Wim A. Buurman
- MHeNs School for Mental Healthy and Neuroscience, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Kaatje Lenaerts
- NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands
| | - Joep P. M. Derikx
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Pediatric Surgery, Emma Children’s Hospital, Amsterdam University Medical Centre, University of Amsterdam, Free University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis H. C. Dejong
- NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Surgery, Maastricht University Medical Centre+, Maastricht, The Netherlands
- Department of Surgery, RWTH University Hospital Aachen, Aachen, Germany
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22
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Zhang M, Zhou Y, Li H, Peng Y, Qiu P, Shi X, Pan X, Liu J. COVID-19: gastrointestinal symptoms from the view of gut-lung axis. Eur J Gastroenterol Hepatol 2021; 33:610-612. [PMID: 33136724 DOI: 10.1097/meg.0000000000001984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The main symptoms of coronavirus disease 2019 (COVID-19) are respiratory manifestations, while some confirmed patients developed gastrointestinal symptoms or even initially presented digestive symptoms. The link between pneumonia and gastrointestinal symptoms caused by severe acute respiratory symptoms coronavirus 2 focused our attention on the concept of 'gut-lung axis'. In this review, we discuss the inevitability and possible mechanisms of the occurrence of intestinal symptoms or intestinal dysfunction in COVID-19 from the perspective of the gut-lung axis, as well as the influence of the imbalance of intestinal homeostasis on the respiratory symptoms of COVID-19. The interaction between lung and intestine might lead to a vicious cycle of pulmonary and intestinal inflammation which may be a potential factor leading to the death of patients with COVID-19.
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Affiliation(s)
- Mengna Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan
| | - Yunjiao Zhou
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan
| | - Haiou Li
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan
| | - Yanan Peng
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan
| | - Peishan Qiu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan
| | - Xianyan Shi
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan
| | - Xingfei Pan
- Department of infectious disease, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jing Liu
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University
- Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, Wuhan
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23
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Strang SG, Breederveld RS, Cleffken BI, Verhofstad MHJ, Van Waes OJF, Van Lieshout EMM. Prevalence of intra-abdominal hypertension and markers for associated complications among severe burn patients: a multicenter prospective cohort study (BURNIAH study). Eur J Trauma Emerg Surg 2021; 48:1137-1149. [PMID: 33721051 PMCID: PMC9001214 DOI: 10.1007/s00068-021-01623-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 02/10/2021] [Indexed: 10/25/2022]
Abstract
PURPOSE Severely burned patients are at risk for intra-abdominal hypertension (IAH) and associated complications such as organ failure, abdominal compartment syndrome (ACS), and death. The aim of this study was to determine the prevalence of IAH among severely burned patients. The secondary aim was to determine the value of urinary intestinal fatty acid binding protein (I-FABP) as early marker for IAH-associated complications. METHODS A prospective observational study was performed in two burn centers in the Netherlands. Fifty-eight patients with burn injuries ≥ 15% of total body surface area (TBSA) were included. Intra-abdominal pressure (IAP) and urinary I-FABP, measured every 6 h during 72 h. Prevalence of IAH, new organ failure and ACS, and the value of urinary intestinal fatty acid binding protein (I-FABP) as early marker for IAH-associated complications were determined. RESULTS Thirty-one (53%) patients developed IAH, 17 (29%) patients developed new organ failure, but no patients developed ACS. Patients had burns of 29% (P25-P75 19-42%) TBSA. Ln-transformed levels of urinary I-FABP and IAP were inversely correlated with an estimate of - 0.06 (95% CI - 0.10 to - 0.02; p = 0.002). Maximal urinary I-FABP levels had a fair discriminatory ability for patients with IAH with an area under the ROC curve of 74% (p = 0.001). Urinary I-FABP levels had no predictive value for IAH or new organ failure in severe burn patients. CONCLUSIONS The prevalence of IAH among patients with ≥ 15% TBSA burned was 53%. None of the patients developed ACS. A relevant diagnostic or predictive value of I-FABP levels in identifying patients at risk for IAH-related complications, could not be demonstrated. LEVEL OF EVIDENCE Level III, epidemiologic and diagnostic prospective observational study.
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Affiliation(s)
- Steven G Strang
- Trauma Research Unit, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Roelf S Breederveld
- Burn Center, Red Cross Hospital, Beverwijk, The Netherlands.,Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands
| | | | - Michael H J Verhofstad
- Trauma Research Unit, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Oscar J F Van Waes
- Trauma Research Unit, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - Esther M M Van Lieshout
- Trauma Research Unit, Department of Surgery, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000 CA, Rotterdam, The Netherlands.
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24
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Wang Q, Li Z, Liu K, Liu J, Chai S, Chen G, Wen S, Ming T, Wang J, Ma Y, Zeng H, Liu C, Xue B. Activation of the G Protein-Coupled Estrogen Receptor Prevented the Development of Acute Colitis by Protecting the Crypt Cell. J Pharmacol Exp Ther 2021; 376:281-293. [PMID: 33318078 DOI: 10.1124/jpet.120.000216] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
G protein-coupled estrogen receptor (GPER) might be involved in ulcerative colitis (UC), but the direct effect of GPER on UC is still unclear. We used male C57BL/6 mice to establish the acute colitis model with administration of dextran sulfate sodium and explored the effect of GPER on acute colitis and its possible mechanism. The selective GPER agonist G-1 inhibited weight loss and colon shortening and decreased the disease activity index for colitis and histologic damage in mice with colitis. All of these effects were prevented by a selective GPER blocker. G-1 administration prevented the dysfunction of tight junction protein expression and goblet cells in colitis model and thus inhibited the increase of mucosal permeability in colitis-suffering mice significantly. GPER activation reduced expression of glucose-regulating peptide-78 and anti-CCAAT/enhancer-binding protein homologous protein and attenuated the three arms of the unfolded protein response in colitis. G-1 therapy inhibited the increase of cleavage caspase-3- and TUNEL-positive cells in colonic crypts in the colitis model, increased the number of Ki67- and bromodeoxyuridine-positive cells in crypts, and reversed the decrease of cyclin D1 and cyclin B1 expression in colitis, indicating its protective effect on crypt cells. In cultured CCD841 cells, G-1 treatment fought against cell injury induced by endoplasmic reticulum stress. These findings demonstrate that GPER activation prevents colitis by protecting the colonic crypt cells, which are associated with inhibition of endoplasmic reticulum stress. SIGNIFICANCE STATEMENT: We demonstrate that G protein-coupled estrogen receptor (GPER) activation prevents dextran sulfate sodium-induced acute colitis by protecting the crypt cells, showing that it inhibited the crypt cell apoptosis and protected proliferation of crypt cells, which resulted in protection of the intestinal mucosal barrier. This protective effect was achieved (at least in part) by inhibiting endoplasmic reticulum stress. Mucosal healing is regarded as a key therapeutic target for colitis, and GPER is expected to become a new therapeutic target for colitis.
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Affiliation(s)
- Qian Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Zhao Li
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Kaixuan Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jianbo Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shiquan Chai
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Guanyu Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Shuyu Wen
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Tian Ming
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Jiayi Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Yuntao Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Honghui Zeng
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Chuanyong Liu
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
| | - Bing Xue
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, China (Q.W., Z.L., K.L., J.L., S.C., G.C., S.W., T.M., H.Z., C.L., B.X.) and Second Clinical Medical College, Lanzhou University, Lanzhou, China (Y.M.)
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25
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Clements TW, Tolonen M, Ball CG, Kirkpatrick AW. Secondary Peritonitis and Intra-Abdominal Sepsis: An Increasingly Global Disease in Search of Better Systemic Therapies. Scand J Surg 2021; 110:139-149. [PMID: 33406974 DOI: 10.1177/1457496920984078] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Secondary peritonitis and intra-abdominal sepsis are a global health problem. The life-threatening systemic insult that results from intra-abdominal sepsis has been extensively studied and remains somewhat poorly understood. While local surgical therapy for perforation of the abdominal viscera is an age-old therapy, systemic therapies to control the subsequent systemic inflammatory response are scarce. Advancements in critical care have led to improved outcomes in secondary peritonitis. The understanding of the effect of secondary peritonitis on the human microbiome is an evolving field and has yielded potential therapeutic targets. This review of secondary peritonitis discusses the history, classification, pathophysiology, diagnosis, treatment, and future directions of the management of secondary peritonitis. Ongoing clinical studies in the treatment of secondary peritonitis and the open abdomen are discussed.
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Affiliation(s)
- T W Clements
- Foothills Medical Centre, Department of Critical Care Medicine and Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - M Tolonen
- HUS Helsinki University Hospital, Helsinki, Finland
| | - C G Ball
- Foothills Medical Centre, Department of Critical Care Medicine and Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - A W Kirkpatrick
- Foothills Medical Centre, Department of Critical Care Medicine and Surgery, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.,Canadian Forces Medical Services, University of Calgary, Calgary, AB, Canada
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26
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Faes S, Hübner M, Demartines N, Hahnloser D. Cytokine clearance in serum and peritoneal fluid of patients undergoing damage control surgery with abdominal negative pressure therapy for abdominal sepsis. Pleura Peritoneum 2020. [PMCID: PMC7790174 DOI: 10.1515/pp-2020-0122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objectives Open abdomen technique with negative pressure therapy (NPT) is widely used in patients with severe abdominal sepsis. The aim of this study was to evaluate cytokine clearance in serum and peritoneal fluid during NPT. Methods This prospective pilot study included six patients with severe abdominal sepsis requiring discontinuity resection and NPT for 48 h followed by planned reoperation. Cytokines (IL6, IL8, IL10, TNFalpha, and IL1beta) were measured in the serum and peritoneal fluid during index operation, on postoperative days 0, 1, and 2. Results Concentrations of cytokines in peritoneal fluid were higher than in serum. IL10 showed a clearance both in serum (to 16.6%, p=0.019) and peritoneal fluid (to 40.9%, p=0.014). IL6 cleared only in serum (to 24.7%, p=0.001) with persistently high levels in peritoneal fluid. IL8 remained high in both serum and peritoneal fluid. TNFalpha and IL1beta were both low in serum with wide range of high peritoneal concentrations. Only TNFalpha in peritoneal fluid showed significant differences between patients with ischemia vs. perforation (p=0.006). Conclusions The present pilot study suggests that cytokines display distinct patterns of clearance or persistence in the peritoneal fluid and serum over the first 48 h of treatment in severe abdominal sepsis with NPT.
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Affiliation(s)
- Seraina Faes
- Department of Visceral Surgery , Lausanne University Hospital CHUV, University of Lausanne (UNIL) , Lausanne , Switzerland
| | - Martin Hübner
- Department of Visceral Surgery , Lausanne University Hospital CHUV, University of Lausanne (UNIL) , Lausanne , Switzerland
| | - Nicolas Demartines
- Department of Visceral Surgery , Lausanne University Hospital CHUV, University of Lausanne (UNIL) , Lausanne , Switzerland
| | - Dieter Hahnloser
- Department of Visceral Surgery , Lausanne University Hospital CHUV, University of Lausanne (UNIL) , Lausanne , Switzerland
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D’Amico R, Siracusa R, Fusco R, Cordaro M, Genovese T, Peritore AF, Gugliandolo E, Crupi R, Impellizzeri D, Cuzzocrea S, Paola RD. Protective effects of Colomast ®, A New Formulation of Adelmidrol and Sodium Hyaluronate, in A Mouse Model of Acute Restraint Stress. Int J Mol Sci 2020; 21:E8136. [PMID: 33143356 PMCID: PMC7662642 DOI: 10.3390/ijms21218136] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 10/28/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
Stress is generally defined as a homeostatic disruption from actual or implied threats and alters the homeostatic balance of different body organs, such as gastrointestinal function and the hypothalamic-pituitary-adrenal axis (HPA), inducing the release of glucocorticoid hormones. Stress is also known to be a risk factor for the development of depression and anxiety. However, until today there are no suitable therapies for treating of stress. The aim of this study was to explore the protective effect of Colomast®, a new preparation containing Adelmidrol, an enhancer of physiological of palmitoylethanolamide (PEA), and sodium hyaluronate in an animal model of immobilization stress. Acute restraint stress (ARS) was induced in mice by fixation for 2 h of the four extremities with an adhesive tape and Colomast® (20 mg/kg) was administered by oral gavage 30 min before the immobilization. Colomast® pre-treatment was able to decrease histopathological changes in the gastrointestinal tract, cytokines expression, neutrophil infiltration, mast cell activation, oxidative stress, as well as modulate nuclear factor NF-kB and apoptosis pathways after ARS induction. Moreover, Colomast® was able to restore tight junction in both ileum and hippocampus and cortex. Additionally, we demonstrated that Colomast® ameliorated depression and anxiety-related behaviours, and modulate inflammatory and apoptosis pathways also in brain after ARS induction. In conclusion, our results suggest Colomast® to be a potential approach to ARS.
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Affiliation(s)
- Ramona D’Amico
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
| | - Roberta Fusco
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
| | - Marika Cordaro
- Department of Biomedical, Dental and Morphological and Functional Imaging University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| | - Tiziana Genovese
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
| | - Alessio Filippo Peritore
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
| | - Enrico Gugliandolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
| | - Rosalia Crupi
- Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy;
| | - Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St Louis, MO 63104, USA
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (R.S.); (R.F.); (T.G.); (A.F.P.); (E.G.); (R.D.P.)
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Estruch G, Martínez-Llorens S, Tomás-Vidal A, Monge-Ortiz R, Jover-Cerdá M, Brown PB, Peñaranda DS. Impact of high dietary plant protein with or without marine ingredients in gut mucosa proteome of gilthead seabream (Sparus aurata, L.). J Proteomics 2020; 216:103672. [PMID: 32004726 DOI: 10.1016/j.jprot.2020.103672] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 12/23/2019] [Accepted: 01/26/2020] [Indexed: 02/08/2023]
Abstract
The digestive tract, particularly the intestine, represents one of the main sites of interactions with the environment, playing the gut mucosa a crucial role in the digestion and absorption of nutrients, and in the immune defence. Previous researches have proven that the fishmeal replacement by plant sources could have an impact on the intestinal status at both digestive and immune level, compromising relevant productive parameters, such as feed efficiency, growth or survival. In order to evaluate the long-term impact of total fishmeal replacement on intestinal mucosa, the gut mucosa proteome was analysed in fish fed with a fishmeal-based diet, against plant protein-based diets with or without alternative marine sources inclusion. Total fishmeal replacement without marine ingredients inclusion, reported a negative impact in growth and biometric parameters, further an altered gut mucosa proteome. However, the inclusion of a low percentage of marine ingredients in plant protein-based diets was able to maintain the growth, biometrics parameters and gut mucosa proteome with similar values to FM group. A total fishmeal replacement induced a big set of underrepresented proteins in relation to several biological processes such as intracellular transport, assembly of cellular macrocomplex, protein localization and protein catabolism, as well as several molecular functions, mainly related with binding to different molecules and the maintenance of the cytoskeleton structure. The set of downregulated proteins also included molecules which have a crucial role in the maintenance of the normal function of the enterocytes, and therefore, of the epithelium, including permeability, immune and inflammatory response regulation and nutritional absorption. Possibly, the amino acid imbalance presented in VM diet, in a long-term feeding, may be the main reason of these alterations, which can be prevented by the inclusion of 15% of alternative marine sources. SIGNIFICANCE: Long-term feeding with plant protein based diets may be considered as a stress factor and lead to a negative impact on digestive and immune system mechanisms at the gut, that can become apparent in a reduced fish performance. The need for fishmeal replacement by alternative ingredients such as plant sources to ensure the sustainability of the aquaculture sector has led the research assessing the intestinal status of fish to be of increasing importance. This scientific work provides further knowledge about the proteins and biologic processes altered in the gut in response to plant protein based diets, suggesting the loss of part of gut mucosa functionality. Nevertheless, the inclusion of alternative marine ingredients was able to reverse these negative effects, showing as a feasible option to develop sustainable aquafeeds.
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Affiliation(s)
- Guillem Estruch
- Aquaculture and Biodiversity Research Group, Institute of Science and Animal Technology, (ICTA), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain
| | - Silvia Martínez-Llorens
- Aquaculture and Biodiversity Research Group, Institute of Science and Animal Technology, (ICTA), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain
| | - Ana Tomás-Vidal
- Aquaculture and Biodiversity Research Group, Institute of Science and Animal Technology, (ICTA), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain
| | - Raquel Monge-Ortiz
- Aquaculture and Biodiversity Research Group, Institute of Science and Animal Technology, (ICTA), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain
| | - Miguel Jover-Cerdá
- Aquaculture and Biodiversity Research Group, Institute of Science and Animal Technology, (ICTA), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain
| | - Paul B Brown
- Department of Forestry and Natural Resources, Purdue University, 715 West State Street, 47907 West Lafayette, IN, USA
| | - David S Peñaranda
- Aquaculture and Biodiversity Research Group, Institute of Science and Animal Technology, (ICTA), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain.
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Voth M, Lustenberger T, Relja B, Marzi I. Is I-FABP not only a marker for the detection abdominal injury but also of hemorrhagic shock in severely injured trauma patients? World J Emerg Surg 2019; 14:49. [PMID: 31832083 PMCID: PMC6868704 DOI: 10.1186/s13017-019-0267-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 09/26/2019] [Indexed: 12/18/2022] Open
Abstract
Background Hemorrhagic shock can lead to intestinal damage with subsequent hyperinflammation and multiple organ dysfunction syndrome (MODS). The intestinal fatty acid-binding protein (I-FABP) is solely expressed in the intestine and is released extracellulary after tissue damage. This study evaluates the validity of I-FABP as an early biomarker to detect hemorrhagic shock and abdominal injury. Patients and methods Severely injured patients with an Injury Severity Score (ISS) ≥ 16 points and an age ≥ 18 years, admitted from January 2010 to December 2016, were included. Overall, 26 patients retrospectively presented with hemorrhagic shock to the emergency room (ER): 8 patients without abdominal injury ("HS noAbd") and 18 patients with abdominal injury ("HS Abd"). Furthermore, 16 severely injured patients without hemorrhagic shock and without abdominal injury ("noHS noAbd") were retrospectively selected as controls. Plasma I-FABP levels were measured at admission to the ER and up to 3 days posttraumatic (d1-d3). Results Median I-FABP levels were significantly higher in the "HS Abd" group compared with the "HS noAbd" group (28,637.0 pg/ml [IQR = 6372.4-55,550.0] vs. 7292.3 pg/ml [IQR = 1282.5-11,159.5], p < 0.05). Furthermore, I-FABP levels of both hemorrhagic shock groups were significantly higher compared with the "noHS noAbd" group (844.4 pg/ml [IQR = 530.0-1432.9], p < 0.05). The time course of I-FABP levels showed a peak on the day of admission with a subsequent decline in the post-traumatic course. Furthermore, significant correlations between I-FABP levels and clinical parameters of hemorrhagic shock, such as hemoglobin, lactate value, systolic blood pressure (SBP), and shock index, were found.The optimal cut-off level of I-FABP for detection of hemorrhagic shock was 1761.9 pg/ml with a sensitivity of 85% and a specificity of 81%. Conclusion This study confirmed our previous observation that I-FABP might be used as a suitable early biomarker for the detection of abdominal injuries in general. In addition, I-FABP may also be a useful and a promising parameter in the diagnosis of hemorrhagic shock, because of reflecting low intestinal perfusion.
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Affiliation(s)
- Maika Voth
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Main, Germany
| | - Thomas Lustenberger
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Main, Germany
| | - Borna Relja
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Main, Germany
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt, Main, Germany
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de Oliveira THC, Souza DG, Teixeira MM, Amaral FA. Tissue Dependent Role of PTX3 During Ischemia-Reperfusion Injury. Front Immunol 2019; 10:1461. [PMID: 31354697 PMCID: PMC6635462 DOI: 10.3389/fimmu.2019.01461] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 06/10/2019] [Indexed: 01/06/2023] Open
Abstract
Reperfusion of an ischemic tissue is the treatment of choice for several diseases, including myocardial infarction and stroke. However, reperfusion of an ischemic tissue causes injury, known as Ischemia and Reperfusion Injury (IRI), that limits the benefit of blood flow restoration. IRI also occurs during solid organ transplantation. During IRI, there is activation of the innate immune system, especially neutrophils, which contributes to the degree of injury. It has been shown that PTX3 can regulate multiple aspects of innate immunity and tissue inflammation during sterile injury, as observed during IRI. In humans, levels of PTX3 increase in blood and elevated levels associate with extent of IRI. In mice, there is also enhanced expression of PTX3 in tissues and plasma after IRI. In general, absence of PTX3, as seen in PTX3-deficient mice, results in worse outcome after IRI. On the contrary, increased expression of PTX3, as seen in PTX3 transgenic mice and after PTX3 administration, is associated with better outcome after IRI. The exception is the gut where PTX3 seems to have a clear deleterious role. Here, we discuss mechanisms by which PTX3 contributes to IRI and the potential of taming this system for the treatment of injuries associated with reperfusion of solid organs.
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Affiliation(s)
| | - Danielle G Souza
- Host-Microorganism Interaction Laboratory, Department of Microbiology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Mauro Martins Teixeira
- Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Flávio Almeida Amaral
- Immunopharmacology Laboratory, Department of Biochemistry and Immunology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Activation of G protein-coupled estrogen receptor protects intestine from ischemia/reperfusion injury in mice by protecting the crypt cell proliferation. Clin Sci (Lond) 2019; 133:449-464. [PMID: 30705108 DOI: 10.1042/cs20180919] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 01/14/2019] [Accepted: 01/30/2019] [Indexed: 12/13/2022]
Abstract
The intestinal ischemia/reperfusion (I/R) injury is a common clinical event related with high mortality in patients undergoing surgery or trauma. Estrogen exerts salutary effect on intestinal I/R injury, but the receptor type is not totally understood. We aimed to identify whether the G protein-coupled estrogen receptor (GPER) could protect the intestine against I/R injury and explored the mechanism. Adult male C57BL/6 mice were subjected to intestinal I/R injury by clamping (45 min) of the superior mesenteric artery followed by 4 h of intestinal reperfusion. Our results revealed that the selective GPER blocker abolished the protective effect of estrogen on intestinal I/R injury. Selective GPER agonist G-1 significantly alleviated I/R-induced intestinal mucosal damage, neutrophil infiltration, up-regulation of TNF-α and cyclooxygenase-2 (Cox-2) expression, and restored impaired intestinal barrier function. G-1 could ameliorate the impaired crypt cell proliferation ability induced by I/R and restore the decrease in villus height and crypt depth. The up-regulation of inducible nitric oxide synthase (iNOS) expression after I/R treatment was attenuated by G-1 administration. Moreover, selective iNOS inhibitor had a similar effect with G-1 on promoting the proliferation of crypt cells in the intestinal I/R model. Both GPER and iNOS were expressed in leucine-rich repeat containing G-protein coupled receptor 5 (Lgr5) positive stem cells in crypt. Together, these findings demonstrate that GPER activation can prompt epithelial cell repair following intestinal injury, which occurred at least in part by inhibiting the iNOS expression in intestinal stem cells (ISCs). GPER may be a novel therapeutic target for intestinal I/R injury.
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Angarita SAK, Duarte S, Russell TA, Ruchala P, Elliott IA, Whitelegge JP, Zarrinpar A. Quantitative Measure of Intestinal Permeability Using Blue Food Coloring. J Surg Res 2019; 233:20-25. [PMID: 30502249 PMCID: PMC6561122 DOI: 10.1016/j.jss.2018.07.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 05/23/2018] [Accepted: 07/02/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Loss of intestinal barrier integrity plays a fundamental role in the pathogenesis of various gastrointestinal diseases and is implicated in the onset of sepsis and multiple organ failure. An array of methods to assess different aspects of intestinal barrier function suffers from lack of sensitivity, prolonged periods of specimen collection, or high expense. We have developed a technique to measure the concentration of the food dye FD&C Blue #1 from blood and sought to assess its utility in measuring intestinal barrier function in humans. MATERIALS AND METHODS Four healthy volunteers and 10 critically ill subjects in the intensive care unit were recruited in accordance with an institutional review board approved protocol. Subjects were given 0.5 mg/kg Blue #1 enterally as an aqueous solution of diluted food coloring. Five blood specimens were drawn per subject: 0 h (before dose), 1, 2, 4, and 8 h. After plasma isolation, organic extracts were analyzed by high-performance liquid chromatography/mass spectrometry detecting the presence of unmodified dye. RESULTS We found no baseline detectable absorption in healthy volunteers. After including the subjects in the intensive care unit, we compared dye absorption in the six subjects who met criteria for septic shock with the eight who did not. Septic patients demonstrated significantly greater absorption of Blue #1 after 2 h. CONCLUSIONS We have developed a novel, easy-to-use method to measure intestinal barrier integrity using a food grade dye detectable by mass spectrometry analysis of patient blood following oral administration.
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Affiliation(s)
- Stephanie A K Angarita
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Sergio Duarte
- Dumont-UCLA Transplant Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Tara A Russell
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Piotr Ruchala
- Semel Institue for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Irmina A Elliott
- Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Julian P Whitelegge
- Semel Institue for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Ali Zarrinpar
- Dumont-UCLA Transplant Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
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Effect of early fluid resuscitation combined with low dose cyclophosphamide on intestinal barrier function in severe sepsis rats. Drug Deliv Transl Res 2018; 8:1254-1264. [PMID: 30112606 DOI: 10.1007/s13346-018-0573-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
To investigate the effect of early fluid resuscitation on intestinal microecology in rats with severe sepsis. The severe sepsis model used was mainly cecal ligation perforation (CLP) model. Male SD rats were randomly divided into five groups: sham, CLP, CLP + normal saline (NS), CLP + cyclophosphamide (CTX), and CLP + NS + CTX. (1) The levels of IL-6, IL-10, and TNF-α in peripheral blood were measured by ELISA. (2) The expression of occludin/β-action in colonic tissue of mice was examined by Western Blot. (3) The intestinal permeability was measured by FD70 detection. (4) The length of the chorionic membrane was measured by colon histopathological staining. (5) The intestinal epithelial cell apoptosis was measured with the apoptosis index. (1) The rat model of severe sepsis was successfully replicated, and the 7-day survival rate of sepsis mice in each group was analyzed. (2) The expression level of splenic junction protein and the pathological damage in colonic tissue of the severe sepsis mice was significantly different between sham, CLP, CTX, NS, and NS + CTX (P < 0.05). The expression of tight junction protein in the NS + CTX mice was the highest, and the pathological damage was the smallest. (3) The colonic tissue apoptosis and intestinal permeability in the severe sepsis mice were compared with those of the colon tissues (P < 0.05). (4) The expression levels of IL-6, IL-10, and TNF-α in peripheral blood were significantly increased after severe sepsis (P < 0.01). The expression of IL-6 and TNF-alpha in each treatment group decreased (P < 0.05), while the expression of IL-10 in NS + CTX group increased significantly (P < 0.01). (1) We successfully replicated the rat model of severe sepsis. (2) Early fluid intervention and cyclophosphamide treatment can significantly improve the 7-day survival rate of the sepsis mice. (3) The fluid resuscitation and cyclophosphamide can delay intestinal damage to the intestinal tract barrier function and play a protective role.
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Rao G, Houson H, Nkepang G, Yari H, Teng C, Awasthi V. Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24. Am J Physiol Gastrointest Liver Physiol 2018; 315:G318-G327. [PMID: 29746173 PMCID: PMC6139642 DOI: 10.1152/ajpgi.00066.2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/02/2018] [Accepted: 05/02/2018] [Indexed: 01/31/2023]
Abstract
Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock. CLEFMA or EF24 (0.4 mg/kg) were given 1 h after withdrawing 50% of blood from Sprague-Dawley rats; no other resuscitation was provided. After another 5 h of compensation, small gut was collected to process tissue for proteasome activity, immunoblotting, and mRNA levels of genes responsible for unfolded-protein response (XBP1, ATF4, glucose-regulated protein of 78/95 kDa, and growth arrest and DNA damage inducible genes 153/34), polyubiquitin B and C, and immunoproteasome subunits β type-8 and -10 and proteasome activator subunit 1. We found that hemorrhagic shock induced proteasome activity in gut tissue and reduced the amounts of ubiquitinated proteins displayed on antiubiquitin immunoblots. However, simultaneous induction of unfolded-protein response or immunoproteasome genes was not observed. CLEFMA and EF24 treatments abolished the hemorrhagic shock-induced increase in proteasome activity. Further investigations revealed that the induction of proteasome in hemorrhagic shock is associated with disassembly of 26S proteasome; CLEFMA and EF24 prevented this disassembly. Consistent with these data, CLEFMA and EF24 reduced hemorrhagic shock-induced degradation of 20S substrate ornithine decarboxylase in gut tissue. These results suggest that activated proteasome plays an important role in ischemic gut pathophysiology, and it can be a druggable target in shock-induced gut dysfunction. NEW & NOTEWORTHY Ischemic injury to the gut is a trigger for the systemic inflammatory response and multiple organ failure in trauma and hemorrhagic shock. We show for the first time that hemorrhagic shock induces the gut proteasome activity by engendering 26S proteasome disassembly. Diphenyldihaloketones 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone treatment prevented the 26S disassembly. Understanding the role of proteasome in shock-associated gut injury will assist in the development of therapeutic means to address it.
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Affiliation(s)
- Geeta Rao
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center , Oklahoma City, Oklahoma
| | - Hailey Houson
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center , Oklahoma City, Oklahoma
| | - Gregory Nkepang
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center , Oklahoma City, Oklahoma
| | - Hooman Yari
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center , Oklahoma City, Oklahoma
| | - Chengwen Teng
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center , Oklahoma City, Oklahoma
| | - Vibhudutta Awasthi
- Department of Pharmaceutical Sciences, University of Oklahoma Health Science Center , Oklahoma City, Oklahoma
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Nicholson SE, Merrill D, Zhu C, Burmeister DM, Zou Y, Lai Z, Darlington DN, Lewis AM, Newton L, Scroggins S, Eastridge BJ, Schwacha MG. Polytrauma independent of therapeutic intervention alters the gastrointestinal microbiome. Am J Surg 2018; 216:699-705. [PMID: 30100050 DOI: 10.1016/j.amjsurg.2018.07.026] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Revised: 06/01/2018] [Accepted: 07/17/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND This study characterizes the gastrointestinal (GI) microbiome in a pre-clinical polytrauma hemorrhage model. METHODS Rats (n = 6) were anesthetized, hemorrhaged 20% of their blood volume, and subjected to a femur fracture and crush injuries to the small intestine, liver, and limb skeletal muscle without resuscitation. Fecal samples were collected pre-injury and 2 h post-injury. Purified DNA from the samples underwent 16s rRNA sequencing for microbial quantification. Bacterial diversity analysis and taxonomic classification were performed. RESULTS Following injury, the gut microbial composition was altered with a shift in beta diversity and significant differences in the relative abundance of taxa. The relative abundance of the families Lachnospiraceae and Mogibacteriaceae was increased at 2 h, while Barnesiellaceae and Bacteroidaceae were decreased. Alpha diversity was unchanged. CONCLUSIONS The GI microbiome is altered in rats subjected to a polytrauma hemorrhage model at 2 h post-injury in the absence of antibiotics or therapeutic interventions.
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Affiliation(s)
- Susannah E Nicholson
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - Daniel Merrill
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - Caroline Zhu
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - David M Burmeister
- The United State Army Institute of Surgical Research, Institute of Surgical Research, 3698 Chambers Pass STE B, JBSA Ft Sam Houston TX 78234-7767, USA.
| | - Yi Zou
- Greehey Children's Cancer Research Institute UT Health San Antonio at San Antonio, 8403 Floyd Curl Dr., San Antonio, TX 78229, USA.
| | - Zhao Lai
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - Daniel N Darlington
- The United State Army Institute of Surgical Research, Institute of Surgical Research, 3698 Chambers Pass STE B, JBSA Ft Sam Houston TX 78234-7767, USA.
| | - Aaron M Lewis
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - Larry Newton
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - Shannon Scroggins
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - Brian J Eastridge
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
| | - Martin G Schwacha
- The University of Texas Health Science Center at San Antonio, Department of Surgery, Division of Trauma and Emergency Surgery, 7703 Floyd Curl Drive (MC 7740), San Antonio, TX 78229-3900, USA.
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Kirkpatrick AW, Coccolini F, Ansaloni L, Roberts DJ, Tolonen M, McKee JL, Leppaniemi A, Faris P, Doig CJ, Catena F, Fabian T, Jenne CN, Chiara O, Kubes P, Manns B, Kluger Y, Fraga GP, Pereira BM, Diaz JJ, Sugrue M, Moore EE, Ren J, Ball CG, Coimbra R, Balogh ZJ, Abu-Zidan FM, Dixon E, Biffl W, MacLean A, Ball I, Drover J, McBeth PB, Posadas-Calleja JG, Parry NG, Di Saverio S, Ordonez CA, Xiao J, Sartelli M. Closed Or Open after Source Control Laparotomy for Severe Complicated Intra-Abdominal Sepsis (the COOL trial): study protocol for a randomized controlled trial. World J Emerg Surg 2018; 13:26. [PMID: 29977328 PMCID: PMC6015449 DOI: 10.1186/s13017-018-0183-4] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 05/10/2018] [Indexed: 12/29/2022] Open
Abstract
Background Severe complicated intra-abdominal sepsis (SCIAS) has an increasing incidence with mortality rates over 80% in some settings. Mortality typically results from disruption of the gastrointestinal tract, progressive and self-perpetuating bio-mediator generation, systemic inflammation, and multiple organ failure. Principles of treatment include early antibiotic administration and operative source control. A further therapeutic option may be open abdomen (OA) management with active negative peritoneal pressure therapy (ANPPT) to remove inflammatory ascites and ameliorate the systemic damage from SCIAS. Although there is now a biologic rationale for such an intervention as well as non-standardized and erratic clinical utilization, this remains a novel therapy with potential side effects and clinical equipoise. Methods The Closed Or Open after Laparotomy (COOL) study will constitute a prospective randomized controlled trial that will randomly allocate eligible surgical patients intra-operatively to either formal closure of the fascia or use of the OA with application of an ANPTT dressing. Patients will be eligible if they have free uncontained intra-peritoneal contamination and physiologic derangements exemplified by septic shock OR a Predisposition-Infection-Response-Organ Dysfunction Score ≥ 3 or a World-Society-of-Emergency-Surgery-Sepsis-Severity-Score ≥ 8. The primary outcome will be 90-day survival. Secondary outcomes will be logistical, physiologic, safety, bio-mediators, microbiological, quality of life, and health-care costs. Secondary outcomes will include days free of ICU, ventilation, renal replacement therapy, and hospital at 30 days from the index laparotomy. Physiologic secondary outcomes will include changes in intensive care unit illness severity scores after laparotomy. Bio-mediator outcomes for participating centers will involve measurement of interleukin (IL)-6 and IL-10, procalcitonin, activated protein C (APC), high-mobility group box protein-1, complement factors, and mitochondrial DNA. Economic outcomes will comprise standard costing for utilization of health-care resources. Discussion Although facial closure after SCIAS is considered the current standard of care, many reports are suggesting that OA management may improve outcomes in these patients. This trial will be powered to demonstrate a mortality difference in this highly lethal and morbid condition to ensure critically ill patients are receiving the best care possible and not being harmed by inappropriate therapies based on opinion only. Trial registration ClinicalTrials.gov, NCT03163095.
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Affiliation(s)
- Andrew W. Kirkpatrick
- Department of Surgery, University of Calgary, Calgary, Alberta Canada
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta Canada
- The Trauma Program, University of Calgary, Calgary, Alberta Canada
| | - Federico Coccolini
- General, Emergency and Trauma Surgery Department, Bufalini Hospital, Cesena, Italy
| | - Luca Ansaloni
- Unit of General and Emergency Surgery, Bufalini Hospital of Cesena, Cesena, Italy
| | - Derek J. Roberts
- Department of Surgery, University of Calgary, Calgary, Alberta Canada
| | - Matti Tolonen
- Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Jessica L. McKee
- Regional Trauma Services, Foothills Medical Centre, Calgary, Alberta Canada
| | - Ari Leppaniemi
- Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Peter Faris
- Research Facilitation Analytics (DIMR), University of Calgary, Calgary, Alberta Canada
| | - Christopher J. Doig
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada
| | - Fausto Catena
- Emergency Surgery Department, Parma University Hospital, Parma, Italy
| | - Timothy Fabian
- Surgery, University of Tennessee Health Sciences Center Memphis, Memphis, TN USA
| | - Craig N. Jenne
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta Canada
| | - Osvaldo Chiara
- General Surgery and Trauma Team Niguarda Hospital Milano, Milan, Italy
| | - Paul Kubes
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta Canada
- Department of Physiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada
- Department of Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada
| | - Braden Manns
- Emergency Surgery Department, Parma University Hospital, Parma, Italy
- Department of Medicine, University of Calgary, Calgary, Alberta Canada
- Libin Cardiovascular Institute and O’Brien Institute of Public Health, University of Calgary, Calgary, Alberta Canada
| | | | - Gustavo P. Fraga
- Division of Trauma Surgery, University of Campinas, Campinas, SP Brazil
| | - Bruno M. Pereira
- Division of Trauma Surgery, University of Campinas, Campinas, SP Brazil
| | - Jose J. Diaz
- Department of Surgery, R Adams Cowley Shock Trauma Center, University of Maryland School on Medicine, Baltimore, MD USA
| | - Michael Sugrue
- Donegal Clinical Research Academy, Letterkenny University Hospital, Donegal, Ireland
| | - Ernest E. Moore
- Trauma and Critical Care Research, University of Colorado, Denver, CO USA
| | - Jianan Ren
- Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Chad G. Ball
- General, Acute Care, and Hepatobiliary Surgery, and Regional Trauma Services, University of Calgary, Calgary, Alberta Canada
| | - Raul Coimbra
- Riverside University Health System Medical Center, Loma Linda, CA USA
- Department of Surgery, Loma Linda University School of Medicine, Loma Linda, CA USA
| | - Zsolt J. Balogh
- John Hunter Hospital and Hunter New England Health District, Newcastle, NSW Australia
- Surgery and Traumatology, University of Newcastle, Newcastle, NSW Australia
| | - Fikri M. Abu-Zidan
- Department of Surgery, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates
| | - Elijah Dixon
- Department of Surgery, University of Calgary, Calgary, Alberta Canada
- Emergency Surgery Department, Parma University Hospital, Parma, Italy
- Surgical Oncology, University of Calgary, Calgary, Alberta Canada
- City Wide Section of General Surgery, University of Calgary, Calgary, Alberta Canada
| | - Walter Biffl
- Scripps Memorial Hospital La Jolla, La Jolla, California USA
| | - Anthony MacLean
- Department of Surgery, University of Calgary, Calgary, Alberta Canada
| | - Ian Ball
- Department of Medicine, Western University, London, Ontario Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario Canada
| | - John Drover
- Department of Critical Care Medicine, Queen’s University, Kingston, Ontario Canada
- Department of Surgery, Queen’s University, Kingston, Ontario Canada
| | - Paul B. McBeth
- Department of Surgery, University of Calgary, Calgary, Alberta Canada
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta Canada
- The Trauma Program, University of Calgary, Calgary, Alberta Canada
| | | | - Neil G. Parry
- Department of Surgery, Western University, Victoria Hospital, London Health Sciences Centre, London, Ontario Canada
- Department of Critical Care, Western University, Victoria Hospital, London Health Sciences Centre, London, Ontario Canada
| | - Salomone Di Saverio
- Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Carlos A. Ordonez
- Department of Surgery, Fundación Valle del Lili and Universidad Del Valle, Cali, Colombia
| | - Jimmy Xiao
- Regional Trauma Services, Foothills Medical Centre, Calgary, Alberta Canada
| | | | - for The Closed Or Open after Laparotomy (COOL) after Source Control for Severe Complicated Intra-Abdominal Sepsis Investigators
- Department of Surgery, University of Calgary, Calgary, Alberta Canada
- Department of Critical Care Medicine, University of Calgary, Calgary, Alberta Canada
- The Trauma Program, University of Calgary, Calgary, Alberta Canada
- General, Emergency and Trauma Surgery Department, Bufalini Hospital, Cesena, Italy
- Unit of General and Emergency Surgery, Bufalini Hospital of Cesena, Cesena, Italy
- Department of Abdominal Surgery, Abdominal Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
- Regional Trauma Services, Foothills Medical Centre, Calgary, Alberta Canada
- Research Facilitation Analytics (DIMR), University of Calgary, Calgary, Alberta Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada
- Emergency Surgery Department, Parma University Hospital, Parma, Italy
- Surgery, University of Tennessee Health Sciences Center Memphis, Memphis, TN USA
- General Surgery and Trauma Team Niguarda Hospital Milano, Milan, Italy
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta Canada
- Department of Physiology, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada
- Department of Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta Canada
- Department of Medicine, University of Calgary, Calgary, Alberta Canada
- Libin Cardiovascular Institute and O’Brien Institute of Public Health, University of Calgary, Calgary, Alberta Canada
- Rambam Health Care Campus, Haifa, Israel
- Division of Trauma Surgery, University of Campinas, Campinas, SP Brazil
- Department of Surgery, R Adams Cowley Shock Trauma Center, University of Maryland School on Medicine, Baltimore, MD USA
- Donegal Clinical Research Academy, Letterkenny University Hospital, Donegal, Ireland
- Trauma and Critical Care Research, University of Colorado, Denver, CO USA
- Department of Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
- General, Acute Care, and Hepatobiliary Surgery, and Regional Trauma Services, University of Calgary, Calgary, Alberta Canada
- Riverside University Health System Medical Center, Loma Linda, CA USA
- Department of Surgery, Loma Linda University School of Medicine, Loma Linda, CA USA
- John Hunter Hospital and Hunter New England Health District, Newcastle, NSW Australia
- Surgery and Traumatology, University of Newcastle, Newcastle, NSW Australia
- Department of Surgery, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates
- Surgical Oncology, University of Calgary, Calgary, Alberta Canada
- City Wide Section of General Surgery, University of Calgary, Calgary, Alberta Canada
- Scripps Memorial Hospital La Jolla, La Jolla, California USA
- Department of Medicine, Western University, London, Ontario Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario Canada
- Department of Critical Care Medicine, Queen’s University, Kingston, Ontario Canada
- Department of Surgery, Queen’s University, Kingston, Ontario Canada
- Department of Surgery, Western University, Victoria Hospital, London Health Sciences Centre, London, Ontario Canada
- Department of Critical Care, Western University, Victoria Hospital, London Health Sciences Centre, London, Ontario Canada
- Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Department of Surgery, Fundación Valle del Lili and Universidad Del Valle, Cali, Colombia
- Department of Surgery, Macerata Hospital, Macerata, Italy
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Ma J, Chen C, Liu Y, Damarla M, Vonakis BM, Guan X, Gao L. Altered expression of TIAM1 in endotoxin-challenged airway epithelial cells and rodent septic models. J Thorac Dis 2018; 10:3187-3195. [PMID: 30069314 PMCID: PMC6051800 DOI: 10.21037/jtd.2018.05.192] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 05/15/2018] [Indexed: 01/19/2023]
Abstract
BACKGROUND In sepsis, reorganization of the actin cytoskeleton in the epithelium during inflammation will lead to a breakdown of epithelial barrier integrity, and contribute to the pathogenesis of sepsis, but the exact changes of various components regulating the actin cytoskeleton pathway remain unclear. METHODS We used lipopolysaccharide (LPS) challenged primary epithelial cells cultured at the air-liquid interface (ALI) to mimic epithelial barrier dysfunction during sepsis. Then we detected differential expression of T-lymphoma invasion and metastasis 1 (TIAM1) gene in lung epithelial cells and septic models. RESULTS LPS induced barrier dysfunction in human tracheobronchial epithelial cells (HTBEs) as measured by statistically significant changes in ionic and macromolecular permeability. We observed differential expression of TIAM1 gene. The protein expression of TIAM1 was decreased after LPS challenge, in human bronchial epithelial cells. Furthermore, the expression levels of both TIAM1 mRNA and protein were decreased in lungs of septic rodent models. CONCLUSIONS Given that expression levels of TIAM1 have been associated with mortality among sepsis patients, our findings have the potential for the development of diagnostic and treatment strategies relevant for patient management.
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Affiliation(s)
- Jie Ma
- Division of Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Chuanxi Chen
- Division of Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Yongjun Liu
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Mahendra Damarla
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
| | - Becky M. Vonakis
- Division of Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
| | - Xiangdong Guan
- Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Li Gao
- Division of Allergy & Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA
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Fallon EA, Biron-Girard BM, Chung CS, Lomas-Neira J, Heffernan DS, Monaghan SF, Ayala A. A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis. J Leukoc Biol 2018; 103:10.1002/JLB.2MIR0917-377R. [PMID: 29393983 PMCID: PMC6314914 DOI: 10.1002/jlb.2mir0917-377r] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 12/26/2017] [Accepted: 01/03/2018] [Indexed: 12/11/2022] Open
Abstract
Coinhibitory molecules, such as PD-1, CTLA-4, 2B4, and BTLA, are an important new family of mediators in the pathophysiology of severe bacterial and/or fungal infection, as well as the combined insults of shock and sepsis. Further, the expression of these molecules may serve as indicators of the immune status of the septic individual. Using PD-1:PD-L as an example, we discuss in this review how such checkpoint molecules may affect the host response to infection by mediating the balance between effective immune defense and immune-mediated tissue injury. Additionally, we explore how the up-regulation of PD-1 and/or PD-L1 expression on not only adaptive immune cells (e.g., T cells), but also on innate immune cells (e.g., macrophages, monocytes, and neutrophils), as well as nonimmune cells during sepsis and/or shock contributes to functional alterations often with detrimental sequelae.
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Affiliation(s)
- Eleanor A. Fallon
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
| | - Bethany M. Biron-Girard
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
| | - Chun-Shiang Chung
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
| | - Joanne Lomas-Neira
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
| | - Daithi S. Heffernan
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
| | - Sean F. Monaghan
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
| | - Alfred Ayala
- Division of Surgical Research, Department of Surgery, Rhode Island Hospital, Brown University, Providence, R.I., USA
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Ji ZP, Li YX, Shi BX, Zhuang ZN, Yang JY, Guo S, Xu XZ, Xu KS, Li HL. Hypoxia preconditioning protects Ca 2+-ATPase activation of intestinal mucosal cells against R/I injury in a rat liver transplantation model. World J Gastroenterol 2018; 24:360-370. [PMID: 29391758 PMCID: PMC5776397 DOI: 10.3748/wjg.v24.i3.360] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 11/07/2017] [Accepted: 11/27/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effect of ischaemia and reperfusion (I/R) injury on the Ca2+-ATPase activation in the intestinal tissue of a rat autologous orthotopic liver transplantation model and to determine if hypoxia preconditioning (HP) therapy induces HIF-1α to protect rat intestinal tissue against I/R injury.
METHODS Rats received non-lethal hypoxic preconditioning therapy to induce HIF-1α expression. We used an autologous orthotopic liver transplantation model to imitate the I/R injury in intestinal tissue. Then, we detected the microstructure changes in small intestinal tissues, Ca2+-ATPase activity, apoptosis, and inflammation within 48 h postoperatively.
RESULTS HIF-1α expression was significantly increased in intestinal tissue at 12 h postoperatively in rats that were exposed to a hypoxic environment for 90 min compared with a non-HP group (HP vs AT, P = 0.0177). Pathological analysis was performed on the intestinal mucosa cells, and the cells in the HP group appeared healthier than the cells in the AT group. The Ca2+-ATPase activity in the small intestinal cells in the AT group was significantly lower after the operation, and the Ca2+-ATPase activity in the HP group recovered faster than that in the AT group at 6 h postoperatively (HP vs AT, P = 0.0106). BCL-2 expression in the HP group was significantly higher than that in the AT group at 12 h postoperatively (HP vs AT P = 0.0010). The expression of the inflammatory factors NO, SOD, IL-6, and TNF-α was significantly lower in the HP group than in the AT group.
CONCLUSION Hypoxia-induced HIF-1α could protect intestinal mucosal cells against mitochondrial damage after I/R injury. HP could improve hypoxia tolerance in small intestinal mucosal cells and increase Ca2+-ATPase activity to reduce the apoptosis of and pathological damage to intestinal cells. HP could be a useful way to promote the earlier recovery of intestinal function after graft procedure.
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Affiliation(s)
- Zhi-Peng Ji
- Department of General Surgery, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
| | - Yuan-Xin Li
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Bao-Xu Shi
- Department of Neurology, People’s Hospital of Rizhaolanshan, Rizhao 276800, Shandong Province, China
| | - Zhuo-Nan Zhuang
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Jing-Yan Yang
- Department of Pathology, the Second Hospital of Shandong University, Jinan 250033, Shandong Province, China
| | - Sen Guo
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan 250033, Shandong Province, China
| | - Xiao-Zhou Xu
- Department of Hepatobiliary Surgery, the Second Hospital of Shandong University, Shandong University, Jinan 250033, Shandong Province, China
| | - Ke-Sen Xu
- Department of Hepatobiliary Surgery, the Second Hospital of Shandong University, Shandong University, Jinan 250033, Shandong Province, China
| | - Hai-Lin Li
- Department of Hepatobiliary Surgery, the Second Hospital of Shandong University, Shandong University, Jinan 250033, Shandong Province, China
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40
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Leenarts CA, Haagmans MJ, Bouwman LH, Sikkink CJ. Severe Abdominal Complaints after Technical Successful Endovascular Treatment of Chronic Splanchnic Ischemia. J Nat Sci Biol Med 2018; 9:100-102. [PMID: 29456403 PMCID: PMC5812064 DOI: 10.4103/jnsbm.jnsbm_200_17] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Reperfusion syndrome (RS) after revascularization of an arterial occlusion of the lower leg is a well-known complication. RS after splanchnic revascularization, however, is an infrequent and less-known phenomenon. We present a patient with persisting abdominal complaints after revascularization of the celiac trunk and superior mesenteric artery suggesting reocclusion. Although computed tomography angiography showed patent splanchnic arteries, an impressive hyperperfusion state of liver and spleen was visualized. Complaints diminished steadily with conservative therapy, but RS can cause severe complications such as liver failure and multiple organ failure. Ignorance of RS might interfere with adequate treatment and can contribute to a high in-hospital mortality rate.
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Affiliation(s)
- Claire A. Leenarts
- Department of Surgery, Zuyderland Medical Center, Sittard-Geleen, Currently at
Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Mark J. Haagmans
- Department of Radiology, Zuyderland Medical Center, Heerlen, The
Netherlands
| | - Lee H. Bouwman
- Department of Surgery, Zuyderland Medical Center, Heerlen, The
Netherlands
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41
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Schellekens DHSM, Hundscheid IHR, Leenarts CAJI, Grootjans J, Lenaerts K, Buurman WA, Dejong CHC, Derikx JPM. Human small intestine is capable of restoring barrier function after short ischemic periods. World J Gastroenterol 2017; 23:8452-8464. [PMID: 29358855 PMCID: PMC5752707 DOI: 10.3748/wjg.v23.i48.8452] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 08/08/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To assess intestinal barrier function during human intestinal ischemia and reperfusion (IR).
METHODS In a human experimental model, 6 cm of jejunum was selectively exposed to 30 min of ischemia (I) followed by 30 and 120 min of reperfusion (R). A sham procedure was also performed. Blood and tissue was sampled at all-time points. Functional barrier function was assessed using dual-sugar absorption tests with lactulose (L) and rhamnose (R). Plasma concentrations of citrulline, an amino acid described as marker for enterocyte function were measured as marker of metabolic enterocytes restoration. Damage to the epithelial lining was assessed by immunohistochemistry for tight junctions (TJs), by plasma marker for enterocytes damage (I-FABP) and analyzed by electron microscopy (EM) using lanthanum nitrate as an electrondense marker.
RESULTS Plasma L/R ratio’s were significantly increased after 30 min of ischemia (30I) followed by 30 min of reperfusion (30R) compared to control (0.75 ± 0.10 vs 0.20 ± 0.09, P < 0.05). At 120 min of reperfusion (120R), ratio’s normalized (0.17 ± 0.06) and were not significantly different from control. Plasma levels of I-FABP correlated with plasma L/R ratios measured at the same time points (correlation: 0.467, P < 0.01). TJs staining shows distortion of staining at 30I. An intact lining of TJs was again observed at 30I120R. Electron microscopy analysis revealed disrupted TJs after 30I with paracellular leakage of lanthanum nitrate, which restored after 30I120R. Furthermore, citrulline concentrations closely paralleled the histological perturbations during intestinal IR.
CONCLUSION This study directly correlates histological data with intestinal permeability tests, revealing that the human gut has the ability of to withstand short episodes of ischemia, with morphological and functional recovery of the intestinal barrier within 120 min of reperfusion.
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Affiliation(s)
- Dirk HSM Schellekens
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
| | - Inca HR Hundscheid
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
| | - Claire AJI Leenarts
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
| | - Joep Grootjans
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
- Department of Gastroenterology, Academic Medical Center, Amsterdam 1105 AZ, the Netherlands
| | - Kaatje Lenaerts
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
| | - Wim A Buurman
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
- MHeNs School of Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
| | - Cornelis HC Dejong
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
| | - Joep PM Derikx
- Department of Surgery, Maastricht University Medical Center, Maastricht 6200 MD, the Netherlands
- NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht 6200 MD, the Netherlands
- Pediatric Surgical Center of Amsterdam, Emma Children's Hospital Academic Medical Center and VU University Medical Center, Amsterdam 1100 DE, the Netherlands
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42
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Hamasaki MY, Machado MCC, Pinheiro da Silva F. Animal models of neuroinflammation secondary to acute insults originated outside the brain. J Neurosci Res 2017; 96:371-378. [DOI: 10.1002/jnr.24184] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 09/11/2017] [Accepted: 09/12/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Mike Yoshio Hamasaki
- Laboratório de Emergências Clínicas, Faculdade de Medicina FMUSP; Universidade de São Paulo; São Paulo SP Brazil
| | | | - Fabiano Pinheiro da Silva
- Laboratório de Emergências Clínicas, Faculdade de Medicina FMUSP; Universidade de São Paulo; São Paulo SP Brazil
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Cen C, McGinn J, Aziz M, Yang WL, Cagliani J, Nicastro JM, Coppa GF, Wang P. Deficiency in cold-inducible RNA-binding protein attenuates acute respiratory distress syndrome induced by intestinal ischemia-reperfusion. Surgery 2017; 162:917-927. [PMID: 28709648 DOI: 10.1016/j.surg.2017.06.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/17/2017] [Accepted: 06/01/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Intestinal ischemia-reperfusion can occur in shock and mesenteric occlusive diseases, causing significant morbidity and mortality. Aside from local injury, intestinal ischemia-reperfusion can result in remote organ damage, particularly in the lungs. Cold-inducible RNA-binding protein (CIRP) was identified as a novel inflammatory mediator. We hypothesized that a deficiency in CIRP would protect the lungs during intestinal ischemia-reperfusion injury. METHODS Intestinal ischemia was induced in adult male C57BL/6 wild-type and CIRP knock-out (CIRP-/-) mice via clamping of the superior mesenteric artery for 60 minutes. Reperfusion was allowed for 4 hours or 20 hours, and blood, gut, and lung tissues were harvested for various analyses. RESULTS After intestinal ischemia-reperfusion, the elevated levels of serum lactate dehydrogenase and inflammatory cytokine interleukin-6 were reduced by 68% and 98%, respectively, at 20 hours after ischemia-reperfusion in CIRP-/- mice compared with the wild-type mice. In the gut, mRNA levels of inflammatory cytokine interleukin-6 were reduced by 67% at 4 hours after ischemia-reperfusion in CIRP-/- mice. In the lungs, inflammatory cytokine interleukin-6 protein and myeloperoxidase activity were reduced by 78% and 26% at 20 hours and 4 hours after ischemia-reperfusion, respectively, in CIRP-/- mice. Finally, the elevated lung caspase-3 was significantly decreased by 55%, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cells decreased by 91%, and lung injury score decreased by 37% in CIRP-/- mice at 20 hours after ischemia-reperfusion. CONCLUSION Increased levels of proinflammatory cytokines, myeloperoxidase, and apoptosis are the hallmarks of acute respiratory distress syndrome. We noticed after intestinal ischemia-reperfusion the proinflammatory milieu in lungs was elevated significantly, while the CIRP-/- mice had significantly decreased levels of proinflammatory cytokine, myeloperoxidase, and apoptotic cells leading to decreased lung injury. These findings strongly established a causal link between CIRP and acute respiratory distress syndrome during intestinal ischemia-reperfusion injuries. Targeting CIRP may therefore be beneficial for treatment of intestinal ischemia-reperfusion-associated acute respiratory distress syndrome acute respiratory distress syndrome.
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Affiliation(s)
- Cindy Cen
- Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY
| | - Joseph McGinn
- Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Weng-Lang Yang
- Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Joaquin Cagliani
- Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY
| | - Jeffrey M Nicastro
- Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY
| | - Gene F Coppa
- Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY
| | - Ping Wang
- Department of Surgery, Hofstra Northwell School of Medicine, Manhasset, NY; Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY.
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Prolonged Cardiopulmonary Bypass is a Risk Factor for Intestinal Ischaemic Damage and Endotoxaemia. Heart Lung Circ 2017; 26:717-723. [DOI: 10.1016/j.hlc.2016.10.012] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 09/21/2016] [Accepted: 10/19/2016] [Indexed: 12/11/2022]
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Inhibition of histone deacetylase 6 restores intestinal tight junction in hemorrhagic shock. J Trauma Acute Care Surg 2017; 81:512-9. [PMID: 27257709 DOI: 10.1097/ta.0000000000001137] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND We recently discovered that Tubastatin-A, a histone deacetylase (HDAC6) inhibitor, can improve survival in a rodent model of hemorrhagic shock (HS), but mechanisms remain poorly defined. In this study, we investigated whether Tubastatin-A could protect intestinal tight junction (TJ) in HS. METHODS In an in-vivo study with Wistar-Kyoto rats, the rats underwent HS (40% blood loss) followed by Tubastatin-A (70 mg/kg) treatment, without fluid resuscitation. The experimental groups were (1) sham (no hemorrhage, no treatment), (2) control (hemorrhage, without treatment), and (3) treatment (hemorrhage with Tubastatin-A administration). Six hours after hemorrhage, ileum was harvested. Whole cell lysate were analyzed for acetylated α-tubulin (Ac-tubulin), total tubulin, acetylated histone 3 at lysine 9 (Ac-H3K9), β-actin, claudin-3 and zonula occludens 1 (ZO-1) proteins by Western blot. Histological effects of Tubastatin-A on small bowel were examined. In an in-vitro study, human intestinal epithelial cells (Caco-2) were divided into three groups: (1) sham (normoxia), (2) control (anoxia, no treatment), and (3) treatment (anoxia, treatment with Tubastatin-A). After 12 hours in an anoxia chamber, the cells were examined for Ac-tubulin and Ac-H3K9, cellular viability, cytotoxicity, claudin-3 and ZO-1 protein expression, and transwell permeability study. RESULTS Tubastatin-A treatment significantly attenuated HS-induced decreases of Ac-tubulin, Ac-H3K9, ZO-1 and claudin-3 proteins in small bowel in-vivo (p < 0.05). In cultured Caco-2 cells, anoxia significantly decreased cellular viability (p < 0.001) and increased cytotoxicity (p < 0.001) compared to the sham group, while Tubastatin-A treatment offered significant protection (p < 0.0001). Moreover, expression of claudin-3 was markedly decreased in vitro compared to the sham group, whereas this was significantly attenuated by Tubastatin-A (p < 0.05). Finally, anoxia markedly increased the permeability of Caco-2 monolayer cells (p < 0.05), while Tubastatin-A significantly attenuated the alteration (p < 0.05). CONCLUSION Inhibition of HDAC6 can induce Ac-tubulin and Ac-H3K9, promote cellular viability, and prevent the loss of intestinal tight junction proteins during HS and anoxia.
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Lipid-rich enteral nutrition controls intestinal inflammation, improves intestinal motility and mucosal barrier damage in a rat model of intestinal ischemia/reperfusion injury. J Surg Res 2017; 213:75-83. [DOI: 10.1016/j.jss.2017.02.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 01/22/2017] [Accepted: 02/14/2017] [Indexed: 01/09/2023]
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Sartelli M, Catena F, Abu-Zidan FM, Ansaloni L, Biffl WL, Boermeester MA, Ceresoli M, Chiara O, Coccolini F, De Waele JJ, Di Saverio S, Eckmann C, Fraga GP, Giannella M, Girardis M, Griffiths EA, Kashuk J, Kirkpatrick AW, Khokha V, Kluger Y, Labricciosa FM, Leppaniemi A, Maier RV, May AK, Malangoni M, Martin-Loeches I, Mazuski J, Montravers P, Peitzman A, Pereira BM, Reis T, Sakakushev B, Sganga G, Soreide K, Sugrue M, Ulrych J, Vincent JL, Viale P, Moore EE. Management of intra-abdominal infections: recommendations by the WSES 2016 consensus conference. World J Emerg Surg 2017; 12:22. [PMID: 28484510 PMCID: PMC5418731 DOI: 10.1186/s13017-017-0132-7] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Accepted: 04/25/2017] [Indexed: 12/18/2022] Open
Abstract
This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.
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Affiliation(s)
| | - Fausto Catena
- Department of Emergency Surgery, Maggiore Hospital, Parma, Italy
| | - Fikri M Abu-Zidan
- Department of Surgery, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates
| | - Luca Ansaloni
- General Surgery Department, Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - Walter L Biffl
- Acute Care Surgery, The Queen's Medical Center, Honolulu, HI USA
| | | | - Marco Ceresoli
- Department of Surgery, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates
| | - Osvaldo Chiara
- Emergency Department, Trauma Center, Niguarda Hospital, Milan, Italy
| | - Federico Coccolini
- Department of Surgery, College of Medicine and Health Sciences, UAE University, Al-Ain, United Arab Emirates
| | - Jan J De Waele
- Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
| | | | - Christian Eckmann
- Department of General, Visceral, and Thoracic Surgery, Klinikum Peine, Academic Hospital of Medical University Hannover, Hannover, Germany
| | - Gustavo P Fraga
- Division of Trauma Surgery, Department of Surgery, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Maddalena Giannella
- Infectious Diseases Unit, Department of Medical and Surgical Sciences, Sant'Orsola Hospital, University of Bologna, Bologna, Italy
| | | | - Ewen A Griffiths
- General and Upper GI Surgery, Queen Elizabeth Hospital, Birmingham, UK
| | - Jeffry Kashuk
- Department of Surgery, Assia Medical Group, Tel Aviv University Sackler School of Medicine, Tel Aviv, Israel
| | - Andrew W Kirkpatrick
- Departments of Surgery, Critical Care Medicine, and the Regional Trauma Service, Foothills Medical Centre, Calgary, AB Canada
| | - Vladimir Khokha
- Department of Emergency Surgery, Mozyr City Hospital, Mozyr, Belarus
| | - Yoram Kluger
- Department of General Surgery, Division of Surgery, Rambam Health Care Campus, Haifa, Israel
| | - Francesco M Labricciosa
- Department of Biomedical Sciences and Public Health, Unit of Hygiene, Preventive Medicine and Public Health, UNIVPM, Ancona, Italy
| | - Ari Leppaniemi
- Abdominal Center, University Hospital Meilahti, Helsinki, Finland
| | - Ronald V Maier
- Department of Surgery, University of Washington, Seattle, WA USA
| | - Addison K May
- Departments of Surgery and Anesthesiology, Division of Trauma and Surgical Critical Care, Vanderbilt University Medical Center, Nashville, TN USA
| | | | - Ignacio Martin-Loeches
- Multidisciplinary Intensive Care Research Organization (MICRO), Wellcome Trust-HRB Clinical Research, Department of Clinical Medicine, Trinity Centre for Health Sciences, St James's University Hospital, Dublin, Ireland
| | - John Mazuski
- Department of Surgery, School of Medicine, Washington University in Saint Louis, St. Louis, MO USA
| | - Philippe Montravers
- Département d'Anesthésie-Réanimation, CHU Bichat Claude-Bernard-HUPNVS, Assistance Publique-Hôpitaux de Paris, University Denis Diderot, Paris, France
| | - Andrew Peitzman
- Department of Surgery, UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA USA
| | - Bruno M Pereira
- Division of Trauma Surgery, Department of Surgery, School of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Tarcisio Reis
- Emergency post-operative Department, Otavio De Freitas Hospital and Osvaldo Cruz Hospital Recife, Recife, Brazil
| | - Boris Sakakushev
- General Surgery Department, Medical University, University Hospital St George, Plovdiv, Bulgaria
| | - Gabriele Sganga
- Department of Surgery, Catholic University of Sacred Heart, Rome, Italy
| | - Kjetil Soreide
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Michael Sugrue
- Letterkenny University Hospital and Donegal Clinical Research Academy, Letterkenny, Ireland
| | - Jan Ulrych
- 1st Department of Surgery, Department of Abdominal, Thoracic Surgery and Traumatology, General University Hospital, Praha, Czech Republic
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium
| | - Pierluigi Viale
- Infectious Diseases Unit, Department of Medical and Surgical Sciences, Sant'Orsola Hospital, University of Bologna, Bologna, Italy
| | - Ernest E Moore
- Department of Surgery, University of Colorado, Denver, CO USA
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Li Y, Xu B, Xu M, Chen D, Xiong Y, Lian M, Sun Y, Tang Z, Wang L, Jiang C, Lin Y. 6-Gingerol protects intestinal barrier from ischemia/reperfusion-induced damage via inhibition of p38 MAPK to NF-κB signalling. Pharmacol Res 2017; 119:137-148. [PMID: 28167239 DOI: 10.1016/j.phrs.2017.01.026] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 01/25/2017] [Indexed: 01/08/2023]
Abstract
Intestinal ischemia reperfusion (I/R) injury caused by severe trauma, intestinal obstruction, and operation is one of the tough challenges in clinic. 6-Gingerol (6G), a main active ingredient of ginger, is found to have anti-microbial, anti-inflammatory, anti-oxidative, and anti-cancer activities. The present study was designed to characterize the potential protective effects of 6G on rat intestinal I/R injury and reveal the correlated mechanisms. Rat intestinal I/R model was established with clamping the superior mesenteric artery (SMA) and 6G was intragastrically administered for three consecutive days before I/R injury. Caco-2 and IEC-6 cells were incubated under hypoxia/reoxygenation (H/R) conditions to simulate I/R injury in vitro. The results showed that 6G significantly alleviated intestinal injury in I/R injured rats by reducing the generation of oxidative stress and inhibiting p38 MAPK signaling pathway. 6G significantly reduced MDA level and increased the levels of SOD, GSH, and GSH-Px in I/R injured intestinal tissues. 6G significantly decreased the production of proinflammatory cytokines including TNF-α, IL-1β, and IL-6, and inhibited the expression of inflammatory mediators iNOS/NO in I/R injured intestinal tissues. The impaired intestinal barrier function was restored by using 6G in I/R injured rats and in both Caco-2 and IEC-6 cells characterized by inhibiting p38 MAPK phosphorylation, nuclear translocation of NF-κB, and expression of myosin light chain kinase (MLCK) protein. 6G also reduced the generation of reactive oxygen species (ROS) in both Caco-2 and IEC-6 cells. In vitro transfection of p38 MAPK siRNA mitigated the impact of 6G on NF-κB and MLCK expression, and the results further corroborated the protective effects of 6G on intestinal I/R injury by repressing p38 MAPK signaling. In conclusion, the present study suggests that 6G exerts protective effects against I/R-induced intestinal mucosa injury by inhibiting the formation of ROS and p38 MAPK activation, providing novel insights into the mechanisms of this therapeutic candidate for the treatment of intestinal injury.
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Affiliation(s)
- Yanli Li
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Bin Xu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Ming Xu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Dapeng Chen
- Laboratory Animal Center, Dalian Medical University, Dalian 116044, China
| | - Yongjian Xiong
- Central Laboratory, The First Affiliated Hospital, Dalian Medical University, Dalian 116044, China
| | - Mengqiao Lian
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Yuchao Sun
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Zeyao Tang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Li Wang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Chunling Jiang
- Department of Physiology, Dalian Medical University, Dalian 116044, China
| | - Yuan Lin
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
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Jaurila H, Koivukangas V, Koskela M, Gäddnäs F, Salo S, Korvala J, Risteli M, Karhu T, Herzig KH, Salo T, Ala-Kokko TI. Inhibitory effects of serum from sepsis patients on epithelial cell migration in vitro: a case control study. J Transl Med 2017; 15:11. [PMID: 28086962 PMCID: PMC5237124 DOI: 10.1186/s12967-016-1110-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/14/2016] [Indexed: 12/05/2022] Open
Abstract
Background Sepsis delays wound re-epithelialization. In this study we explored the effect of human sepsis sera as well as the effects of cytokines, growth factors and exosomes of sepsis sera treated normal fibroblasts (NF) on keratinocyte migration and proliferation in vitro. Methods Serum samples were taken on days 1, 4, and 9 from 44 patients diagnosed with severe sepsis, and from 14 matching healthy controls. We evaluated the effects of sepsis serum with or without TNF-α, EGF, EGF receptor inhibitor or exosomes of sepsis sera treated NF on human keratinocyte (HaCaT) proliferation (BrdU assay), viability (MTT assay), and migration (horizontal wound healing model). Cytokine levels of sepsis and healthy sera were measured by multiplex assay. Comparisons between groups were carried out using SPSS statistics and P < 0.05 was considered significant. Results Severe-sepsis sera collected on days 1, 4, and 9 reduced keratinocyte proliferation by 6% (P = 0.005), 20% (P = 0.001), and 18% (P = 0.002), respectively, compared to control sera. Cell viability in cultures exposed to sepsis sera from days 4 and 9 was reduced by 38% (P = 0.01) and 58% (P < 0.001), respectively. Open-surface wounds exposed to sepsis sera from days 1 and 4 were larger than those exposed to sera from healthy controls (60 vs. 31%, P = 0.034 and 66 vs. 31%, P = 0.023, respectively). Exosomes of sepsis or healthy sera treated NF inhibited keratinocyte migration. We detected higher serum levels of cytokines TNF-α (5.7 vs. 0.7 pg/ml, P < 0.001), IL-6 (24.8 vs. 3.8 pg/ml, P < 0.001), IL-10 (30.0 vs. 11.9 pg/ml, P = 0.040), and VEGF (177.9 vs. 48.1 pg/ml, P = 0.018) in sepsis sera. Levels of EGF were significantly lower in sepsis sera than in that of healthy controls (6.5 vs. 115.6 pg/ml, P < 0.001). Sepsis serum supplemented with EGF 5 ng/ml and TNF-α in all concentrations improved keratinocyte migration. Conclusions Keratinocyte viability, proliferation and migration were reduced in severe sepsis in vitro. Exosomes from NF added in healthy or sepsis serum media inhibited keratinocyte migration. Decreased levels of EGF in sepsis sera may partially explain the delay of wound healing with severe-sepsis patients. Increased levels of TNF-α in sepsis sera do not explain diminished keratinocyte migration.
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Affiliation(s)
- Henna Jaurila
- Research Group of Surgery, Anesthesia and Intensive Care, Oulu University Hospital, P. O. Box 21, 90029, Oulu, Finland. .,Cancer and Translational Medicine Research Unit, Faculty of Medicine, Medical Research Center Oulu, University of Oulu, P.O. Box 5281, 90014, Oulu, Finland.
| | - Vesa Koivukangas
- Research Group of Surgery, Anesthesia and Intensive Care, Oulu University Hospital, P. O. Box 21, 90029, Oulu, Finland
| | - Marjo Koskela
- Research Group of Surgery, Anesthesia and Intensive Care, Oulu University Hospital, P. O. Box 21, 90029, Oulu, Finland
| | - Fiia Gäddnäs
- Research Group of Surgery, Anesthesia and Intensive Care, Oulu University Hospital, P. O. Box 21, 90029, Oulu, Finland
| | - Sirpa Salo
- Research Group of Biomedicine, Faculty of Biochemistry and Molecular Medicine, University of Oulu, P. O. Box 5000, Oulu, 90014, Finland
| | - Johanna Korvala
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, Medical Research Center Oulu, University of Oulu, P.O. Box 5281, 90014, Oulu, Finland
| | - Maija Risteli
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, Medical Research Center Oulu, University of Oulu, P.O. Box 5281, 90014, Oulu, Finland
| | - Toni Karhu
- Research Unit of Biomedicine, Faculty of Medicine and Biocenter of Oulu, University of Oulu, P.O. Box 5000, Oulu, 90014, Finland
| | - Karl-Heinz Herzig
- Research Unit of Biomedicine, Faculty of Medicine and Biocenter of Oulu, University of Oulu, P.O. Box 5000, Oulu, 90014, Finland.,Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Collegium Maius, Fredry 10, 61-701, Poznan, Poland
| | - Tuula Salo
- Cancer and Translational Medicine Research Unit, Faculty of Medicine, Medical Research Center Oulu, University of Oulu, P.O. Box 5281, 90014, Oulu, Finland.,Research Group of Oral Health Sciences, Oulu University Hospital, Medical Research Center Oulu, University of Oulu, P. O. Box 5000, Oulu, 90014, Finland
| | - Tero I Ala-Kokko
- Research Group of Surgery, Anesthesia and Intensive Care, Oulu University Hospital, P. O. Box 21, 90029, Oulu, Finland
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Shu XL, Yu TT, Kang K, Zhao J. Effects of glutamine on markers of intestinal inflammatory response and mucosal permeability in abdominal surgery patients: A meta-analysis. Exp Ther Med 2016; 12:3499-3506. [PMID: 28105083 PMCID: PMC5228558 DOI: 10.3892/etm.2016.3799] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 07/14/2016] [Indexed: 01/20/2023] Open
Abstract
The present meta-analysis was carried out to determine whether supplementation with glutamine (Gln) would reduce the intestinal inflammatory response and mucosal permeability in patients undergoing abdominal surgery. The PubMed, EMBASE, Web of Science, and The Cochrane Library databases were searched for randomized controlled trials on the effects of supplementation with Gln, and published from August, 1966 to June 2014. Inclusion criteria for the meta-analysis were: i) Study design was a randomized controlled trial, ii) study included patients undergoing abdominal surgery, iii) study patients received a supplementation with Gln peptide (Ala-Gln or Gly-Gln) whereas control patients did not use any supplements, and iv) study outcomes included inflammatory markers [C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6, and IL-2 receptor] and markers of intestinal permeability [lactulose/mannitol, diamine oxidase, D(−)lactic acid, and endotoxin]. Qualities of controlled trials were assessed using the Jadad score. Meta-analyses were performed with fixed- or random-effect models depending on the heterogeneity of studies. There were 21 trials meeting the inclusion criteria. The meta-analysis revealed that the levels of CRP, TNF-α, and IL-6 in patients supplemented with Gln were significantly lower than those in control patients, whereas the levels of IL-2 receptor were increased by Gln supplementation. Gln also significantly decreased the lactulose/mannitol ratio, the levels of diamine oxidase and endotoxin, and tended to decrease the levels of cyclic D-lactic acid. In conclusion, Gln appears to effectively reduce the inflammatory response and intestinal mucosal permeability in patients after abdominal surgery.
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Affiliation(s)
- Xiao-Liang Shu
- Department of Nutrition, Jinshan Hospital, Fudan University School of Medicine, Shanghai 201508, P.R. China
| | - Ting-Ting Yu
- Tongji University School of Medicine, Shanghai 200092, P.R. China
| | - Kai Kang
- Tongji University School of Medicine, Shanghai 200092, P.R. China
| | - Jian Zhao
- Tongji University School of Medicine, Shanghai 200092, P.R. China
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