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Meza Monge K, Rosa C, Sublette C, Pratap A, Kovacs EJ, Idrovo JP. Navigating Hemorrhagic Shock: Biomarkers, Therapies, and Challenges in Clinical Care. Biomedicines 2024; 12:2864. [PMID: 39767770 PMCID: PMC11673713 DOI: 10.3390/biomedicines12122864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 12/13/2024] [Accepted: 12/15/2024] [Indexed: 01/04/2025] Open
Abstract
Hemorrhagic shock remains a leading cause of preventable death worldwide, with mortality patterns varying significantly based on injury mechanisms and severity. This comprehensive review examines the complex pathophysiology of hemorrhagic shock, focusing on the temporal evolution of inflammatory responses, biomarker utility, and evidence-based therapeutic interventions. The inflammatory cascade progresses through distinct phases, beginning with tissue injury and endothelial activation, followed by a systemic inflammatory response that can transition to devastating immunosuppression. Recent advances have revealed pattern-specific responses between penetrating and blunt trauma, necessitating tailored therapeutic approaches. While damage control resuscitation principles and balanced blood product administration have improved outcomes, many molecular targeted therapies remain investigational. Current evidence supports early hemorrhage control, appropriate blood product ratios, and time-sensitive interventions like tranexamic acid administration. However, challenges persist in biomarker validation, therapeutic timing, and implementation of personalized treatment strategies. Future directions include developing precision medicine approaches, real-time monitoring systems, and novel therapeutic modalities while addressing practical implementation barriers across different healthcare settings. Success in hemorrhagic shock management increasingly depends on integrating multiple interventions across different time points while maintaining focus on patient-centered outcomes.
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Affiliation(s)
- Kenneth Meza Monge
- Department of Surgery, Division of G.I, Trauma, and Endocrine Surgery, University of Colorado, Aurora, CO 80045, USA; (K.M.M.); (C.R.); (C.S.); (A.P.); (E.J.K.)
| | - Caleb Rosa
- Department of Surgery, Division of G.I, Trauma, and Endocrine Surgery, University of Colorado, Aurora, CO 80045, USA; (K.M.M.); (C.R.); (C.S.); (A.P.); (E.J.K.)
| | - Christopher Sublette
- Department of Surgery, Division of G.I, Trauma, and Endocrine Surgery, University of Colorado, Aurora, CO 80045, USA; (K.M.M.); (C.R.); (C.S.); (A.P.); (E.J.K.)
| | - Akshay Pratap
- Department of Surgery, Division of G.I, Trauma, and Endocrine Surgery, University of Colorado, Aurora, CO 80045, USA; (K.M.M.); (C.R.); (C.S.); (A.P.); (E.J.K.)
| | - Elizabeth J. Kovacs
- Department of Surgery, Division of G.I, Trauma, and Endocrine Surgery, University of Colorado, Aurora, CO 80045, USA; (K.M.M.); (C.R.); (C.S.); (A.P.); (E.J.K.)
- Department of Immunology and Microbiology, University of Colorado, Aurora, CO 80045, USA
| | - Juan-Pablo Idrovo
- Department of Surgery, Division of G.I, Trauma, and Endocrine Surgery, University of Colorado, Aurora, CO 80045, USA; (K.M.M.); (C.R.); (C.S.); (A.P.); (E.J.K.)
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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, et alKirkpatrick 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:] [Show More Authors] [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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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, et alKirkpatrick 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] [Show More Authors] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [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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4
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Zhao X, Wang LY, Tang CY, Li K, Huang YH, Duan YR, Zhang ST, Ke K, Su BH, Yang W. Electro-microenvironment modulated inhibition of endogenous biofilms by piezo implants for ultrasound-localized intestinal perforation disinfection. Biomaterials 2023; 295:122055. [PMID: 36805242 DOI: 10.1016/j.biomaterials.2023.122055] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 02/08/2023] [Accepted: 02/12/2023] [Indexed: 02/16/2023]
Abstract
Endogenous bacterial infections from damaged gastrointestinal (GI) organs have high potential to cause systemic inflammatory responses and life-threatening sepsis. Current treatments, including systemic antibiotic administration and surgical suturing, are difficult in preventing bacterial translocation and further infection. Here, we report a wireless localized stimulator composed of a piezo implant with high piezoelectric output serving as an anti-infective therapy patch, which aims at modulating the electro-microenvironment of biofilm around GI wounds for effective inhibition of bacterial infection if combined with ultrasound (US) treatment from outside the body. The pulsed charges generated by the piezo implant in response to US stimulation transfer into bacterial biofilms, effectively destroying their macromolecular components (e.g., membrane proteins), disrupting the electron transport chain of biofilms, and inhibiting bacterial proliferation, as proven by experimental studies and theoretical calculations. The piezo implant, in combination with US stimulation, also exhibits successful in vivo anti-infection efficacy in a rat cecal ligation and puncture (CLP) model. The proposed strategy, combining piezo implants with controllable US activation, creates a promising pathway for inhibiting endogenous bacterial infection caused by GI perforation.
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Affiliation(s)
- Xing Zhao
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Li-Ya Wang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chun-Yan Tang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, Sichuan, China
| | - Kai Li
- Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, 610041, Chengdu, China
| | - Yan-Hao Huang
- School of Materials Science and Engineering, Chongqing Jiao Tong University, Chongqing, 400074, China
| | - Yan-Ran Duan
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Shu-Ting Zhang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, Sichuan, China
| | - Kai Ke
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, Sichuan, China.
| | - Bai-Hai Su
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Wei Yang
- College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, Sichuan, China.
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5
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Ho JW, Quan C, Gauger MA, Alam HB, Li Y. ROLE OF PEPTIDYLARGININE DEIMINASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN INJURIES: FUTURE NOVEL DIAGNOSTICS AND THERAPEUTIC TARGETS. Shock 2023; 59:247-255. [PMID: 36597759 PMCID: PMC9957939 DOI: 10.1097/shk.0000000000002052] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
ABSTRACT Injuries lead to an early systemic inflammatory state with innate immune system activation. Neutrophil extracellular traps (NETs) are a complex of chromatin and proteins released from the activated neutrophils. Although initially described as a response to bacterial infections, NETs have also been identified in the sterile postinjury inflammatory state. Peptidylarginine deiminases (PADs) are a group of isoenzymes that catalyze the conversion of arginine to citrulline, termed citrullination or deimination. PAD2 and PAD4 have been demonstrated to play a role in NET formation through citrullinated histone 3. PAD2 and PAD4 have a variety of substrates with variable organ distribution. Preclinical and clinical studies have evaluated the role of PADs and NETs in major trauma, hemorrhage, burns, and traumatic brain injury. Neutrophil extracellular trap formation and PAD activation have been shown to contribute to the postinjury inflammatory state leading to a detrimental effect on organ systems. This review describes our current understanding of the role of PAD and NET formation following injury and burn. This is a new field of study, and the emerging data appear promising for the future development of targeted biomarkers and therapies in trauma.
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Affiliation(s)
- Jessie W. Ho
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Chao Quan
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI
| | - Megan A. Gauger
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Hasan B. Alam
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Yongqing Li
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI
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Bogner-Flatz V, Braunstein M, Bazarian JJ, Keil L, Richter PH, Kusmenkov T, Biberthaler P, Giese T. Neutrophil Gene Expression Patterns in Multiple Trauma Patients Indicate Distinct Clinical Outcomes. J Surg Res 2022; 277:100-109. [DOI: 10.1016/j.jss.2022.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 12/23/2021] [Accepted: 03/10/2022] [Indexed: 10/18/2022]
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Ultraporous Polyquaternium-Carboxylated Chitosan Composite Hydrogel Spheres with Anticoagulant, Antibacterial, and Rapid Endotoxin Removal Profiles for Sepsis Treatment. Biomacromolecules 2022; 23:3728-3742. [PMID: 35926229 DOI: 10.1021/acs.biomac.2c00583] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hemoperfusion is an important method to remove endotoxins and save the lives of patients with sepsis. However, the current adsorbents for hemoperfusion have disadvantages of insufficient endotoxin adsorption capacity, poor blood compatibility, and so on. Herein, we proposed a novel emulsion templating (ET) method to prepare ultraporous and double-network carboxylated chitosan (CCS)-poly(diallyl dimethylammonium chloride) (PDDA) hydrogel spheres (ET-CCSPD), bearing both negative and positive charges. CCS was introduced to balance the strong positive charges of PDDA to improve hemocompatibility, and emulsion templates endowed the adsorbent with an ultraporous structure for enhanced adsorption efficacy. The ET-CCSPDs neither damaged blood cells nor activated complement responses. In addition, the activated partial thromboplastin time (APTT) was prolonged to 8.5 times, which was beneficial for reducing the injection of anticoagulant in patients. The ET-CCSPDs had excellent scavenging performance against bacteria and endotoxin, with removal ratios of 96.7% for E. coli and 99.8% for S. aureus, respectively, and the static removal ratio of endotoxin in plasma was as high as 99.1% (C0 = 5.50 EU/mL, critical illness level). An adsorption cartridge filled with the ET-CCSPDs could remove 84.7% of endotoxin within 1 h (C0 = 100 EU/mL in PBS). Interestingly, the ET-CCSPDs had a good inhibitory effect on the cytokines produced by endotoxin-mediated septic blood. By developing the ET method to prepare ultraporous and double-network adsorbents, the problems of low adsorption efficiency and poor blood compatibility of traditional endotoxin adsorbents have been solved, thus opening a new route to fabricate absorbents for blood purification.
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Walsh SA, Davis TA. Key early proinflammatory signaling molecules encapsulated within circulating exosomes following traumatic injury. J Inflamm (Lond) 2022; 19:6. [PMID: 35551611 PMCID: PMC9097360 DOI: 10.1186/s12950-022-00303-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 03/26/2022] [Indexed: 12/28/2022] Open
Abstract
Background Assessment of immune status in critically ill patients is often based on serial tracking of systemic cytokine levels and clinical laboratory values. Exosomes are extracellular vesicles that can be secreted and internalized by cells to transport important cellular cargo in the regulation of numerous physiological and pathological processes. Here, we characterize the early compartmentalization profile of key proinflammatory mediators in serum exosomes in the steady state and following trauma. Adult male Sprague-Dawley rats (91 including naïve) were divided into one of four traumatic injury model groups incorporating whole-body blast, fracture, soft-tissue crush injury, tourniquet-induced ischemia, and limb amputation. Serum was collected at 1, 3, 6, and 24 h, and 3- and 7-day post-injury. Electrochemiluminescence-based immunoassays for 9 key proinflammatory mediators in whole serum, isolated serum exosomes, and exosome depleted serum were analyzed and compared between naïve and injured rats. Serum clinical chemistry analysis was performed to determine pathological changes. Results In naïve animals, substantial amounts of IL-1β, IL-10, and TNF-α were encapsulated, IL-6 was completely encapsulated, and CXCL1 freely circulating. One hour after blast injury alone, levels of exosome encapsulated IFN-γ, IL-10, IL-6, IL-13, IL-4, and TNF-α increased, whereas freely circulating and membrane-associated levels remained undetectable or low. Rats with the most severe polytraumatic injuries with end organ complications had the earliest rise and most pronounced concentration of IL-1β, IL-10, TNF-α, and IL-6 across all serum compartments. Moreover, CXCL1 levels increased in relation to injury severity, but remained almost entirely freely circulating at all timepoints. Conclusion These findings highlight that conventional ELISA-based assessments, which detect only free circulating and exosome membrane-bound mediators, underestimate the full immunoinflammatory response to trauma. Inclusion of exosome encapsulated mediators may be a better, more accurate and clinically useful early strategy to identify, diagnose, and monitor patients at highest risk for post-traumatic inflammation-associated complications.
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Affiliation(s)
- Sarah A Walsh
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA
| | - Thomas A Davis
- Department of Surgery, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
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Cheng X, Shen X, Wang M, Li J, Li G. TNFAIP8 modulates the survival and immune activity of Th17 cells via p53/ p21/ MDM2 pathway after acute insult. Cytokine X 2022; 4:100062. [PMID: 35128379 PMCID: PMC8803581 DOI: 10.1016/j.cytox.2022.100062] [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: 01/12/2021] [Revised: 09/26/2021] [Accepted: 01/13/2022] [Indexed: 10/25/2022] Open
Abstract
Th17 cells induced immunosuppression plays a vital role in sepsis. As a member of the tumor necrosis factor α induced protein 8 (TNFAIP8) family, TNFAIP8 is associated with different physiopathological conditions with immunological responses. However, its potential roles in regulating Th17 cells after the acute insult have not been fully elucidated. In this study, sepsis was induced by cecal ligation and puncture (CLP) in the male adult C57BL/6 mice. The stable TNFAIP8 knockdown (KD) Th17 cells were established by infecting with lentivirus carrying TNFAIP8-specific shRNA. CCK-8 assay was conducted to evaluate Th17 cell proliferation, and Annexin V/7-AAD assay was applied for apoptosis measurement by flow cytometry. The alterations of p53/ p21/ MDM2 pathway were assessed by Western blot. We observed that a high TNFAIP8 expression level was related to acute injury in septic mice. TNFAIP8 silencing suppressed Th17 cell proliferation and cytokine production in vivo and in vitro. In addition, TNFAIP8 KD increased Th17 cell apoptosis in septic mice. Furthermore, TNFAIP8 seems to affect the immune function of Th17 cells by regulating p53/ p21/ MDM2 signaling processes. We found that TNFAIP8 KD caused the up-regulation of P21 and MDM2, and also elevated p53 protein level during sepsis. Pharmacological inhibition of p53 partially rescued cell proliferation and apoptotic effects of TNFAIP8 KD. In summary, our work suggests that TNFAIP8 modulates the survival and immune function of Th17 cells after acute insult, which was possibly mediated through the p53/ p21/ MDM2 pathway.
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Affiliation(s)
- Xiaobin Cheng
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
| | - Xiaocheng Shen
- Department of Intensive Care Unit, Wuxi Fifth People's Hospital, China
| | - Min Wang
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
| | - Jing Li
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
| | - Gang Li
- Department of Intensive Care Unit, Hubei Provincial Hospital of Traditional Chinese Medicine, China
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Levels of Biological Markers of Nitric Oxide in Serum of Patients with Mandible Fractures. J Clin Med 2021; 10:jcm10132832. [PMID: 34206954 PMCID: PMC8268335 DOI: 10.3390/jcm10132832] [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: 05/13/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 11/16/2022] Open
Abstract
Background: Nitric oxide is a small gaseous molecule with significant bioactivity. It has been observed that NO may have a dual role dependent on its production and concentrations in the bone microenvironment. The objective of the study was to assess the concentration of total nitric oxide malonyldialdehyde, nitrotyrosine, and asymmetric dimethylarginine in the serum of patients with mandibular fractures and to understand the relationship between these compounds, in order to expand the knowledge base of the role of nitric oxide and its activity indicators in the process of bone fracture healing. Material and Methods: The study included 20 patients with mandibular fractures who were undergoing inpatient and outpatient treatments and a control group of 15 healthy people. Results were analyzed with respect to the measurement time. Total nitric oxide concentration in the blood serum was determined according to the Griess reaction, while the concentration of malonyldialdehyde, nitrotyrosine, and asymmetric dimethylarginine was estimated using the immunoenzymatic method (i.e., enzyme-linked immunosorbent assay). Results: Before the procedure, as well as on the first day and 2 and 6 weeks after the procedure, higher concentrations of total nitric oxide and lower concentrations of malonyldialdehyde were observed in the blood serum of patients with mandibular fractures compared to the control group. No statistically significant differences were found in nitrotyrosine concentrations in the blood serum of patients throughout the measurement period. However, a significantly higher asymmetric dimethylarginine concentration was observed in the patient serum before the procedure and on the first day of operation as compared with the control group. Analysis of the results observed in patient serum with respect to the number of fractures within the mandible demonstrated the same trend of concentrations for the tested compounds for the entire study group. Conclusions: In summary, our results revealed that the intensity of local processes resulting from mandibular fractures is associated with the concentration of nitric oxide, confirming its significant role, as well as that of its indicators, in the process of bone fracture healing in this patient population.
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11
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Walsh SA, Hoyt BW, Rowe CJ, Dey D, Davis TA. Alarming Cargo: The Role of Exosomes in Trauma-Induced Inflammation. Biomolecules 2021; 11:biom11040522. [PMID: 33807302 PMCID: PMC8065643 DOI: 10.3390/biom11040522] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/26/2021] [Accepted: 03/29/2021] [Indexed: 12/11/2022] Open
Abstract
Severe polytraumatic injury initiates a robust immune response. Broad immune dysfunction in patients with such injuries has been well-documented; however, early biomarkers of immune dysfunction post-injury, which are critical for comprehensive intervention and can predict the clinical course of patients, have not been reported. Current circulating markers such as IL-6 and IL-10 are broad, non-specific, and lag behind the clinical course of patients. General blockade of the inflammatory response is detrimental to patients, as a certain degree of regulated inflammation is critical and necessary following trauma. Exosomes, small membrane-bound extracellular vesicles, found in a variety of biofluids, carry within them a complex functional cargo, comprised of coding and non-coding RNAs, proteins, and metabolites. Composition of circulating exosomal cargo is modulated by changes in the intra- and extracellular microenvironment, thereby serving as a homeostasis sensor. With its extensively documented involvement in immune regulation in multiple pathologies, study of exosomal cargo in polytrauma patients can provide critical insights on trauma-specific, temporal immune dysregulation, with tremendous potential to serve as unique biomarkers and therapeutic targets for timely and precise intervention.
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Affiliation(s)
- Sarah A. Walsh
- USU Walter Reed Surgery, Uniformed Services University, Bethesda, MD 20814, USA; (S.A.W.); (B.W.H.); (C.J.R.); (D.D.)
| | - Benjamin W. Hoyt
- USU Walter Reed Surgery, Uniformed Services University, Bethesda, MD 20814, USA; (S.A.W.); (B.W.H.); (C.J.R.); (D.D.)
| | - Cassie J. Rowe
- USU Walter Reed Surgery, Uniformed Services University, Bethesda, MD 20814, USA; (S.A.W.); (B.W.H.); (C.J.R.); (D.D.)
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Devaveena Dey
- USU Walter Reed Surgery, Uniformed Services University, Bethesda, MD 20814, USA; (S.A.W.); (B.W.H.); (C.J.R.); (D.D.)
- Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA
| | - Thomas A. Davis
- USU Walter Reed Surgery, Uniformed Services University, Bethesda, MD 20814, USA; (S.A.W.); (B.W.H.); (C.J.R.); (D.D.)
- Correspondence:
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12
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Secretome Conveys the Protective Effects of ASCs: Therapeutic Potential Following Hemorrhagic Shock? Shock 2019; 50:442-448. [PMID: 29112105 DOI: 10.1097/shk.0000000000001047] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
OBJECTIVES We tested whether resuscitation supplemented with rat adipose-derived stem cells (ASCs) or secretome (conditioned media) of ASCs can ameliorate inflammation, cell/organ injury, and/or improve outcome after hemorrhagic traumatic shock (HTS). INTERVENTIONS Rats were subjected to HTS and a resuscitation protocol that mimics prehospital restrictive reperfusion followed by an adequate reperfusion phase. Twenty minutes into the restrictive reperfusion, animals received an intravenous bolus of 2 × 10 cells (ASC group) or the secretome produced by 2 × 10 ASCs/24 h (ASC-Secretome group). Controls received the vehicle (Vehicle group). All rats were observed for 28-day survival. MEASUREMENTS AND MAIN RESULTS HTS-induced inflammation represented by IL-6 was inhibited in the ASC (80%, P < 0.001) and in ASC-Secretome (59%, P < 0.01) group at 48 h compared with Vehicle group. At 24 h, HTS-induced liver injury reflected in plasma alanine aminotransferase was ameliorated by 36% (P < 0.001) in both the ASC and ASC-Secretome groups when compared with the Vehicle. There was no effect on kidney function and/or general cell injury markers. HTS induced a moderate 28-day mortality (18%) that was prevented (P = 0.08) in the ASC but not in the ASC-Secretome group (12%). CONCLUSIONS Our data suggest that the ASC-secretome supplemented resuscitation following HTS, in the absence of the stem cells, exerts anti-inflammatory and liver protective effects. Given its ease of preparation, storage, availability, and application (in contrast to the stem cells) we believe that the cell-free secretome has a better therapeutic potential in the early phase of an acute hemorrhagic shock scenario.
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Mejía-Terrazas GE, Ruíz-Suárez M, Vadillo-Ortega F, Franco Y Bourland RE, López-Muñoz E. Effect of interscalene nerve block on the inflammatory response in shoulder surgery: a randomized trial. J Shoulder Elbow Surg 2019; 28:e291-e303. [PMID: 31227466 DOI: 10.1016/j.jse.2019.02.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 02/18/2019] [Accepted: 02/27/2019] [Indexed: 02/01/2023]
Abstract
BACKGROUND Comparing techniques of general anesthesia and regional anesthesia in arthroscopic shoulder surgery, some studies have shown differences in the intensity of immediate postoperative pain and neuroendocrine response, but the inflammatory response when using balanced general anesthesia (BGA) vs. an ultrasound-guided (USG) single-dose interscalene block (SDIB) has not been compared. MATERIALS AND METHODS In a single-center, prospective, randomized clinical trial, the inflammatory response of 2 groups of 10 patients scheduled to undergo arthroscopic shoulder surgery was evaluated through measurement of a panel of cytokines that act on cells of the adaptive immune response to promote or inhibit inflammation, chemokines involved in chemotaxis, the erythrocyte sedimentation rate (ESR), the high-sensitivity C-reactive protein (CRP) level, and the white blood cell (WBC) count in 3 blood samples (before anesthesia, immediately postoperatively, and 24 hours postoperatively) with 2 types of anesthesia (BGA vs. USG SDIB). Postoperative pain intensity (immediately, at 12 hours, and at 24 hours) was also assessed. RESULTS The ESR and CRP level increased significantly at 24 hours after surgery; however, the increase in ESR (P < .0001) and CRP level (P < .0001) was lower in the USG SDIB group. Significant increases in the levels of soluble interleukin 2 receptor α (P = .022) and interleukin 12p40 (P = .016) occurred in the immediate postoperative period in the USG SDIB group. Immediate postoperative pain showed a significant increase (P < .001) in the BGA group. CONCLUSIONS In arthroscopic shoulder surgery, the use of a USG SDIB compared with the use of BGA is possibly associated with improved pain control in the immediate postoperative period and lower immunosuppression, even at 24 hours after surgery.
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Affiliation(s)
| | - Michell Ruíz-Suárez
- Traumatology Service, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra," Mexico City, Mexico
| | - Felipe Vadillo-Ortega
- Unit of Vinculation, Faculty of Medicine, Universidad Nacional Autónoma de México and Laboratory of Metabolism and Nutrition in Experimental Medicine, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | | | - Eunice López-Muñoz
- Medical Research Unit in Reproductive Medicine, Unidad Médica de Alta Especialidad, Hospital de Gineco Obstetricia No. 4, "Luis Castelazo Ayala," Instituto Mexicano del Seguro Social, Mexico City, Mexico
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Polydatin prevents LPS-induced acute kidney injury through inhibiting inflammatory and oxidative responses. Microb Pathog 2019; 137:103688. [PMID: 31445125 DOI: 10.1016/j.micpath.2019.103688] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 08/19/2019] [Accepted: 08/21/2019] [Indexed: 12/27/2022]
Abstract
The anti-inflammatory property of polydatin, a natural active ingredient found in the rhizome of Polygonum cuspidatum, has been verified. Although a variety of physiological functions have been uncovered, the protective effects and mechanism of polydatin on LPS-induced acute kidney injury remain unclear. Kidney histological change, MDA content, MPO activity, TNF-α, IL-1β, and IL-6 production were measured in this study. Furthermore, NF-κB and Nrf2 were tested by western blotting. In this study, polydatin not only significantly attenuated serum creatinine and BUN levels, but also remarkably inhibited TNF-α, IL-1β, and IL-6 production, MPO activity, and MDA content. Polydatin significantly inhibited LPS-induced NF-κB activation. Also, polydatin significantly increased Nrf2 and HO-1 expression. Taken together, all the above results indicate that polydatin had protective effects against LPS-induced AKI by blocking inflammatory and oxidative responses.
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Zhou RX, Dai W, Hu CL. Differential clinical benefits of continuous blood purification treatment in critically ill patients with variable APACHE II scores. Exp Ther Med 2019; 18:741-746. [PMID: 31281452 DOI: 10.3892/etm.2019.7617] [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: 03/05/2018] [Accepted: 09/27/2018] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to assess whether the Acute Physiology And Chronic Health Evaluation (APACHE) II score may be used to predict whether critically ill patients benefit from continuous blood purification (CBP) treatment. A total of 115 critically ill patients were retrospectively reviewed and grouped according to their baseline APACHE II scores. Each group was further divided into 2 groups based on whether they received CBP or not. At 72 h after CBP treatment, clinical indicators comprising the plasma levels of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8, as well as endotoxin and procalcitonin (PCT), and severity scores (APACHE II, multiple organ dysfunction syndrome and systemic inflammatory response syndrome), were analyzed in all patients. It was observed that while CBP slightly reduced the severity scores in all patients, it significantly improved those in patients with an APACHE II score of 20-29 (P<0.05). Similarly, the plasma levels of TNF-α, IL-6, IL-8, endotoxin and PCT were significantly lower in patients receiving CBP than in those without CBP when the APACHE II score was 20-29 (P<0.05). Furthermore, CBP treatment significantly decreased the fatality rate and length of stay at the intensive care unit (ICU) for critically ill patients with an APACHE II score of 20-29 (P<0.05). In conclusion, CBP significantly decreases the inflammatory response, shortens the length of stay at the ICU and improves the prognosis for critically ill patients with an APACHE II score of 20-29 points. This observation suggests that the APACHE II score is an important clinical indicator to determine the potential benefit of CBP therapy in critically ill patients.
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Affiliation(s)
- Rui-Xiang Zhou
- Intensive Care Unit of The First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Wei Dai
- Intensive Care Unit of The First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
| | - Chao-Liang Hu
- Intensive Care Unit of The First Hospital of Wuhan, Wuhan, Hubei 430022, P.R. China
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Xiong W, Ouyang J, Ci H, Jiang W, Han W, Fu Y, Tian P. The predictive value of serum neopterin for multiple organ dysfunction syndrome in severe burn patients. Pteridines 2018. [DOI: 10.1515/pteridines-2018-0019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Objective To investigate the predictive value of serum neopterin for multiple organ dysfunction syndrome (MODS) in severe burn patients. Methods Seventy-six severe burn patients with burns covering a total body surface area (TBSA) above 70% were included in this study. Of the 76 patients, 29 cases developed MODS (MODS group) and the remaining 47 subjects did not (non-MODS group). From the MODS group, 12 patients died (Death group) and 17 patients survived (Survive group). The serum level of neopterin in the MODS and non-MODS groups were examined by radioimmunoassay on following 1, 3 , 7 , 14 , 21 and 28 post-burn days (PBDs). A receiver operating characteristic (ROC) curve was used to analyse the predictive value of serum neopterin for MODS and death. Results The serum neopterin level in the MODS group was significantly higher than that of non-MODS group between 3~28 PBDs (p<0.001). However, the serum neopterin levels between the MODS and non-MODS groups following 1 PBD were not statistically significant (p>0.05). The best diagnostic performance of serum neopterin for MODS occurred 14 PBDs with the prediction sensitivity and specificity of 75.86% (56.46%~89.70%) and 85.11% (71.69%~93.80%) respectively. However, serum neopterin levels had no clinical value in predicting the death of MODS patients. The area under the ROC curve (AUC) was 0.72 (0.58~0.85), 0.81 (0.71~0.92) and 0.83 (0.72~0.94) for serum neopterin as biomarker in the prediction of MODS after 3, 7 and 14 PBDs, respectively. The AUCs were 0.50 (0.27~0.73), 0.53 (0.30~0.76) and 0.56 (0.33~0.79) for serum neopterin as biomarker in prediction of death for MODS patients after 3, 7 and 14 PBDs, respectively. Conclusion The persistent and significant increase of serum neopterin level is closely related to the development of MODS in patients with severe burns. Serum neopterin is therefore a promising serological marker for MODS early diagnosis, but has little efficacy in the prediction of the likelihood of death in severe burn patients with MODS.
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Affiliation(s)
- Wei Xiong
- Department of Burn and Plastic Surgery, the First Affiliated Hospital of Shlhezi University, Shlhezl , China
| | - Jun Ouyang
- Department of Emergency, the First Affiliated Hospital of Shihezi University, Shihezi , China
| | - Hai Ci
- Department of Burn and Plastic Surgery, the First Affiliated Hospital of Shihezi University, Shihezi , China
| | - Wenping Jiang
- Department of Burn and Plastic Surgery, the First Affiliated Hospital of Shihezi University, Shihezi , China
| | - Wei Han
- Department of Burn and Plastic Surgery, the First Affiliated Hospital of Shihezi University, Shihezi , China
| | - Yu Fu
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Shihezi University, Shihezi , China
| | - Peigang Tian
- Department of ICU, the First Affiliated Hospital of Shihezi University, Shihezi , China
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17
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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, for The Closed Or Open after Laparotomy (COOL) after Source Control for Severe Complicated Intra-Abdominal Sepsis Investigators. 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: 59] [Impact Index Per Article: 8.4] [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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Complement C5a Alters the Membrane Potential of Neutrophils during Hemorrhagic Shock. Mediators Inflamm 2018; 2018:2052356. [PMID: 30002598 PMCID: PMC5996468 DOI: 10.1155/2018/2052356] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 02/26/2018] [Accepted: 04/01/2018] [Indexed: 12/17/2022] Open
Abstract
Background Polymorphonuclear granulocytes (PMN) play a crucial role in host defense. Physiologically, exposure of PMN to the complement activation product C5a results in a protective response against pathogens, whereas in the case of systemic inflammation, excessive C5a substantially impairs neutrophil functions. To further elucidate the inability of PMN to properly respond to C5a, this study investigates the role of the cellular membrane potential of PMN in response to C5a. Methods Electrophysiological changes in cellular and mitochondrial membrane potential and intracellular pH of PMN from human healthy volunteers were determined by flow cytometry after exposure to C5a. Furthermore, PMN from male Bretoncelles-Meishan-Willebrand cross-bred pigs before and three hours after severe hemorrhagic shock were analyzed for their electrophysiological response. Results PMN showed a significant dose- and time-dependent depolarization in response to C5a with a strong response after one minute. The chemotactic peptide fMLP also evoked a significant shift in the membrane potential of PMN. Acidification of the cellular microenvironment significantly enhanced depolarization of PMN. In a clinically relevant model of porcine hemorrhagic shock, the C5a-induced changes in membrane potential of PMN were markedly diminished compared to healthy littermates. Overall, these membrane potential changes may contribute to PMN dysfunction in an inflammatory environment.
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Analysis of selected pro- and anti-inflammatory cytokines in patients with multiple injuries in the early period after trauma. Cent Eur J Immunol 2018; 43:42-49. [PMID: 29731691 PMCID: PMC5927172 DOI: 10.5114/ceji.2018.74872] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/25/2016] [Indexed: 02/07/2023] Open
Abstract
Introduction Severe trauma causes damage to the protective barriers of the organism, and thus activates immunological reaction. Among substances secreted during this process pro-inflammatory cytokines are of high importance. The aim of the study Severe trauma causing multiple injuries is more likely to lead to particularly intensive inflammatory reaction, which can sometimes lead to serious complications, even life-threatening. The aim of the study is to determine those parameters which may serve as predictors of infectious complications and to enable estimation of the patient's immunological status before the decision to introduce elective procedures. Material and methods The study population included patients with multiple trauma treated in the Department of Trauma Surgery of the Medical University of Gdańsk. The severity of injuries was evaluated with commonly used numerical scales (Revised Trauma Score - RTS, Injury Severity Score - ISS, Glasgow Coma Scale - GCS). Blood samples were collected on the first, second, and fifth day after injury. Evaluated parameters: C-reactive protein (CRP), the level of cytokines: IL-8, IL-1β, IL-6, TNF, IL-12p70, and IL-10. Control population: individuals without injury. Results Evaluation of IL-6, IL-8, and CRP levels in patients with multiple trauma in the early period after injury (2-3 days) could be considered as a predictor of delayed infection (5-10 days). CRP level, being cheap and commonly accessible, can be used in clinical practice enabling identification of patients at higher risk of infectious complications and introduction of appropriate treatment and prevention. The analysis of the mentioned parameters may contribute to choosing an appropriate management strategy, including "timing" depending on the patient's biological status.
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Bouboulis G, Bonatsos VG, Katsarou AI, Karameris A, Galanos A, Zacharioudaki A, Theodoropoulos G, Zografos G, Papalois AE, Toutouzas K. Experimental Hemorrhagic Shock Protocol in Swine Models: The Effects of 21-Aminosteroid on the Small Intestine. Curr Ther Res Clin Exp 2018; 88:18-25. [PMID: 29632620 PMCID: PMC5889707 DOI: 10.1016/j.curtheres.2018.03.003] [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] [Accepted: 03/05/2018] [Indexed: 11/03/2022] Open
Abstract
Background The protective potential of lazaroids has been reported in previous studies on ischemia/reperfusion and induced hemorrhagic shock protocols. Objectives The present study is the first experimental protocol on the effects of the antioxidant factor U-74389G on the small intestine of swine models in a hemorrhagic shock protocol and resuscitation with 3 different types of fluids. Methods The study included 49 Landrace breed swine that were divided into groups of 7 each. Hemorrhage was provoked 45 minutes after starting the surgical protocol (0 minutes), followed by resuscitation starting 30 minutes after haemorrhage ceased by using 3 different fluids. Three groups (Group A, resuscitation using blood; Group B, resuscitation with Ringer’s lactate solution; and Group C, resuscitation with hypertonic saline solution) underwent resuscitation with fluid alone, and another 3 groups (named A', B,' and C') were administered lazaroid U-74389G in addition to fluid. Control Group S underwent all the surgical procedures without hemorrhagic shock. Vital signs, complete blood count, and biochemical markers were analyzed, and tissue samples of the small intestine were collected from all animals. Further, malondialdehyde, tumor necrosis factor-α, and levels of inflammation in the tissue sample were measured. Results In Group S-A-A' and Group S-C-C', the analysis did not show statistically significant differences in the percentage changes of histopathology, malondialdehyde, and tumor necrosis factor-α through time. In Group S-B-B', the malondialdehyde levels in the small intestine were reduced in both the B and B' groups, without lazaroid (Group B) (P = 0.038) and lazaroid (Group B') (P = 0.011), compared with Group S (control), but the group without lazaroid (Group B) had greater reduction in malondialdehyde levels than the group treated with lazaroid (Group B'). With regard to the biochemistry results, 24% reduction was observed for alkaline phosphatase (P = 0.022) in Group A' treated with lazaroid compared with that in the untreated group. Lastly, for the complete blood count parameters, a 14% reduction in white blood cells was observed in Group B', which was treated with lazaroid in all phases (P = 0.015) (absolute value = 6.23) compared with Group B (absolute value = 13.74). Conclusions Despite few initial findings of this study suggesting that administration of lazaroid U-74389G may have some potential in attenuation of the effects of hemorrhagic shock in the small intestine of swine models, no differences remained after correction for multiple comparisons was made. Therefore, further research is required to investigate this result thoroughly.
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Affiliation(s)
| | | | - Ageliki I Katsarou
- Laboratory of Chemistry‑Biochemistry‑Physical Chemistry of Foods, Department of Dietetics and Nutrition, School of Health Science and Education, Harokopio University, Kallithea, Athens, Greece
| | | | - Antonis Galanos
- Laboratory of Research of the Musculoskeletal System, School of Medicine, University of Athens, Athens, Greece
| | | | - George Theodoropoulos
- First Department of Propaedeutic Surgery, Hippokratio Hospital, University of Athens, Athens, Greece
| | - George Zografos
- First Department of Propaedeutic Surgery, Hippokratio Hospital, University of Athens, Athens, Greece
| | | | - Konstantinos Toutouzas
- First Department of Propaedeutic Surgery, Hippokratio Hospital, University of Athens, Athens, Greece
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21
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Yamamoto K, Yamamoto T, Takamura M, Usui S, Murai H, Kaneko S, Taniguchi T. Effects of mineralocorticoid receptor antagonists on responses to hemorrhagic shock in rats. World J Crit Care Med 2018; 7:1-8. [PMID: 29430402 PMCID: PMC5797971 DOI: 10.5492/wjccm.v7.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 12/03/2017] [Accepted: 12/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the effects of mineralocorticoid receptor (MR) antagonists on mortality and inflammatory responses after hemorrhagic shock (HS) in rats.
METHODS One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone (EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha (TNF-α) concentrations, and arterial blood gas at 8 h after HS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery.
RESULTS The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups (P = 0.888).
CONCLUSION Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.
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Affiliation(s)
- Kanako Yamamoto
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Takashi Yamamoto
- Department of Anesthesiology and Intensive Care Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Masayuki Takamura
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Soichiro Usui
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Hisayoshi Murai
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Shuichi Kaneko
- Department of System Biology, Kanazawa University Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
| | - Takumi Taniguchi
- Department of Anesthesiology and Intensive Care Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-8641, Japan
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22
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Carr ZJ, Van De Louw A, Fehr G, Li JD, Kunselman A, Ruiz-Velasco V. Increased whole blood FFA2/GPR43 receptor expression is associated with increased 30-day survival in patients with sepsis. BMC Res Notes 2018; 11:41. [PMID: 29338778 PMCID: PMC5771199 DOI: 10.1186/s13104-018-3165-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 01/12/2018] [Indexed: 12/18/2022] Open
Abstract
Objective Sepsis is a condition associated with a dysregulated inflammatory response to infection with significant morbidity. Recent advances have elucidated the vital role that the short chain fatty acid glycoprotein receptor 43 (FFA2/GPR43) plays in inflammatory and immunomodulatory pathways. We hypothesized that elevated whole blood GPR43 RNA expression would be associated with increased 30-day survival in patients admitted with sepsis. Patients (n = 93) admitted to the intensive care unit with the diagnosis of sepsis underwent quantitative real time PCR within 48 h of intensive care unit admission. Clinical and demographical parameters were retrospectively extracted from the chart and compared to quantitative measurements of GPR43 RNA expression. Results Utilizing logistic regression, we found that the odds of mortality decreased for every one-unit increase in GPR43 RNA expression for patients that survived to 30 days [OR = 0.71; 95% CI (0.50, 0.99) p = 0.049]. Using linear regression, we determined that the increase in whole blood GPR43 expression was not associated with whole blood white cell count [r = 0.04; 95% CI (−0.16, 0.24); p = 0.70] or body mass index [r = − 0.07; 95% CI (− 0.23, 0.18); p = 0.81]. We conclude that the GPR43 receptor plays an integral role in survival during and after sepsis.
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Affiliation(s)
- Zyad J Carr
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA.
| | - Andry Van De Louw
- Division of Pulmonary & Critical Care Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA
| | - Graham Fehr
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA
| | - Jialiu D Li
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA
| | - Allen Kunselman
- Department of Public Health Sciences, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, 17033, USA
| | - Victor Ruiz-Velasco
- Department of Anesthesiology & Perioperative Medicine, Penn State Milton S. Hershey Medical Center, H187, 500 University Dr., Hershey, PA, 17033, USA
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23
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Paredes RM, Reyna S, Vernon P, Tadaki DK, Dallelucca JJ, Sheppard F. Generation of complement molecular complex C5b-9 (C5b-9) in response to poly-traumatic hemorrhagic shock and evaluation of C5 cleavage inhibitors in non-human primates. Int Immunopharmacol 2017; 54:221-225. [PMID: 29156357 DOI: 10.1016/j.intimp.2017.10.033] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/28/2017] [Accepted: 10/30/2017] [Indexed: 01/08/2023]
Abstract
Severe trauma initiates a systemic inflammatory cascade and that involves early activation of complement and cleavage of C5 into C5a (anaphylatoxin) and C5b (C5b-9 membrane attack complex). We examined activation of C5 in non-human primate (NHP) models of hemorrhagic shock. Blood plasma concentrations of C5b-9 were significantly increased in NHPs in response to hemorrhage alone and were further increased with the addition of tissue trauma. The onset of increased C5 cleavage was accelerated in NHPs that experienced decompensated poly-traumatic hemorrhagic shock. Next, to identify an effective inhibitor of NHP C5 cleavage in vitro, as a first step in the development of a potential therapy, three inhibitors of human C5 cleavage and hemolysis were tested in vitro. NHP C5 cleavage and complement-mediated hemolysis were successfully inhibited by pre-treatment of serum samples with a small, inhibitory peptide RA101348. Commercially-available C5 inhibitory antibodies were found to exhibit species-specific efficacy in vitro. Quidel's A217 antibody demonstrated dose-dependent inhibition of C5 cleavage and hemolysis in NHP samples, whereas LGM-Eculizumab only inhibited complement-mediated hemolysis in human samples. This study shows that complement activation in NHPs following experimental poly-traumatic hemorrhagic shock is consistent with clinical reports, and that cleavage of C5 and complement-mediated hemolysis can be effectively inhibited in vitro using a small peptide inhibitor. Taken together, these findings offer a clinically-relevant vehicle and a potential strategy for treatment of hemorrhagic shock with poly-traumatic injury.
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Affiliation(s)
- R Madelaine Paredes
- Naval Medical Research Unit San Antonio, JBSA-Ft. Sam Houston, TX, United States.
| | - Sarah Reyna
- Naval Medical Research Unit San Antonio, JBSA-Ft. Sam Houston, TX, United States
| | - Philip Vernon
- Naval Medical Research Unit San Antonio, JBSA-Ft. Sam Houston, TX, United States
| | - Douglas K Tadaki
- Naval Medical Research Unit San Antonio, JBSA-Ft. Sam Houston, TX, United States
| | - Jurandir J Dallelucca
- Chemical & Biological Technologies Department, Defense Threat Reduction Agency, Fort Belvoir, VA, United States
| | - Forest Sheppard
- Naval Medical Research Unit San Antonio, JBSA-Ft. Sam Houston, TX, United States
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24
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Bahrami A, Jafarmadar M, Redl H, Bahrami S, Jiang JX. TNF-α release capacity is suppressed immediately after hemorrhage and resuscitation. Chin J Traumatol 2017; 20:207-211. [PMID: 28684036 PMCID: PMC5555245 DOI: 10.1016/j.cjtee.2016.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Revised: 04/05/2017] [Accepted: 04/12/2017] [Indexed: 02/04/2023] Open
Abstract
PURPOSE It has been suggested that patients with traumatic insults are resuscitated into a state of an early systemic inflammatory response. We aimed to evaluate the influence of hemorrhagic shock and resuscitation (HSR) upon the inflammatory response capacity assessed by overall TNF-α secretion capacity of the host compared to its release from circulating leukocytes in peripheral circulation. METHODS Rats (8/group) subjected to HS (MAP of 30-35 mmHg for 90 min followed by resuscitation over 50 min) were challenged with Lipopolysaccharide (LPS), 1 μg/kg intravenously at the end of resuscitation (HSR-LPS group) or 24 h later (HSR-LPS24 group). Control animals were injected with LPS without bleeding (LPS group). Plasma TNF-α was measured at 90 min after the LPS challenge. In addition, whole blood (WB) was obtained either from healthy controls (CON) immediately after resuscitation (HSR), or at 24 h post-shock (HSR 24). WB was incubated with LPS (100 ng/mL) for 2 h at 37 °C. TNF-α concentration and LPS binding capacity (LBC) was determined. RESULTS Compared to LPS group, HSR followed by LPS challenge resulted in suppression of plasma TNF-α in HSR-LPS and HSR-LPS24 groups (1835 ± 478, 273 ± 77, 498 ± 200 pg/mL, respectively). Compared to CON the LPS-induced TNF-α release capacity of circulating leukocytes ex vivo was strongly declined both at the end of resuscitation (HSR) and 24 h later (HSR24) (1012 ± 259, 313 ± 154, 177 ± 63 ng TNF/mL, respectively). The LBC in WB was similar between CON and HSR and only moderately enhanced in HSR24 (57 ± 6, 56 ± 6, 71 ± 5 %, respectively). CONCLUSION Our data suggest that the overall inflammatory response capacity is decreased immediately after HSR, persisting up to 24 h, and is independent of LBC.
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Affiliation(s)
- Arian Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, 1200 Vienna, Austria
| | - Mohammad Jafarmadar
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, 1200 Vienna, Austria
| | - Heinz Redl
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, 1200 Vienna, Austria
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, 1200 Vienna, Austria,Corresponding author. Fax: +43 59393 41982.
| | - Jian-Xin Jiang
- State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China
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25
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Kozlov AV, Lancaster JR, Meszaros AT, Weidinger A. Mitochondria-meditated pathways of organ failure upon inflammation. Redox Biol 2017; 13:170-181. [PMID: 28578275 PMCID: PMC5458092 DOI: 10.1016/j.redox.2017.05.017] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 05/24/2017] [Accepted: 05/24/2017] [Indexed: 02/06/2023] Open
Abstract
Liver failure induced by systemic inflammatory response (SIRS) is often associated with mitochondrial dysfunction but the mechanism linking SIRS and mitochondria-mediated liver failure is still a matter of discussion. Current hypotheses suggest that causative events could be a drop in ATP synthesis, opening of mitochondrial permeability transition pore, specific changes in mitochondrial morphology, impaired Ca2+ uptake, generation of mitochondrial reactive oxygen species (mtROS), turnover of mitochondria and imbalance in electron supply to the respiratory chain. The aim of this review is to critically analyze existing hypotheses, in order to highlight the most promising research lines helping to prevent liver failure induced by SIRS. Evaluation of the literature shows that there is no consistent support that impaired Ca++ metabolism, electron transport chain function and ultrastructure of mitochondria substantially contribute to liver failure. Moreover, our analysis suggests that the drop in ATP levels has protective rather than a deleterious character. Recent data suggest that the most critical mitochondrial event occurring upon SIRS is the release of mtROS in cytoplasm, which can activate two specific intracellular signaling cascades. The first is the mtROS-mediated activation of NADPH-oxidase in liver macrophages and endothelial cells; the second is the acceleration of the expression of inflammatory genes in hepatocytes. The signaling action of mtROS is strictly controlled in mitochondria at three points, (i) at the site of ROS generation at complex I, (ii) the site of mtROS release in cytoplasm via permeability transition pore, and (iii) interaction with specific kinases in cytoplasm. The systems controlling mtROS-signaling include pro- and anti-inflammatory mediators, nitric oxide, Ca2+ and NADPH-oxidase. Analysis of the literature suggests that further research should be focused on the impact of mtROS on organ failure induced by inflammation and simultaneously providing a new theoretical basis for a targeted therapy of overwhelmed inflammatory response.
Relationship between mitochondrial dysfunction and high lethality upon sepsis. Criteria to define critical for lethality mitochondrial dysfunction. ATP, calcium, mitochondrial ultrastructure and apoptosis, upon inflammation. Regulation of inflammatory processes by mitochondrial ROS.
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Affiliation(s)
- Andrey V Kozlov
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Donaueschingen Str. 13, 1200 Vienna, Austria.
| | - Jack R Lancaster
- University of Pittsburgh, Departments of Pharmacology & Chemical Biology, Surgery, and Medicine, 1341A Thomas E. Starzl Biomedical Science Tower, PA 15261, United States
| | - Andras T Meszaros
- University of Szeged, Institute of Surgical Research, 6720 Szeged, Hungary
| | - Adelheid Weidinger
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Donaueschingen Str. 13, 1200 Vienna, Austria
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26
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Ding C, Li F, Long Y, Zheng J. Chloroquine attenuates lipopolysaccharide-induced inflammatory responses through upregulation of USP25. Can J Physiol Pharmacol 2016; 95:481-491. [PMID: 28134560 DOI: 10.1139/cjpp-2016-0303] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Lipopolysaccharide (LPS) is a key pathogenic factor in sepsis, and its recognition by toll-like receptor 4 (TLR4) can activate two district signaling pathways, leading to activation of transcription factors including NF-κB and interferon regulatory factor 3 (IRF3). Chloroquine (CQ) has been shown to affect LPS-TLR4 colocalization and inhibit both MyD88-dependent and TRAM/TRIF-dependent pathways, though the mechanism involved is still poorly understood. Here, we found that the ubiquitin-proteasome system might be involved in this process. CQ increased USP25, a deubiquitinating enzyme, as well as mRNA and protein expression in a dose-dependent manner, which might to some degree be involved in CQ attenuation of LPS-induced macrophage activation. Overexpression of USP25 decreased LPS-induced inflammatory cytokines like TNF-α, IL-6, and IFN-β, while specific siRNA-mediated USP25 silencing increased TNF-α, IL-6, and IFN-β production and secretion. In addition, USP25 deletion strengthened mitogen-activated protein kinase (MAPKs) phosphorylation and IκB degradation. Moreover, USP25 interference increased NF-κB and IRF3 nuclear translocation. Taken together, our data demonstrated a new possible regulator of LPS-induced macrophage activation mediated by CQ, through upregulation of USP25.
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Affiliation(s)
- Changyu Ding
- Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.,Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China
| | - Fangfang Li
- Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.,Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China
| | - Yupeng Long
- Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.,Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China
| | - Jiang Zheng
- Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China.,Medical Research Center, Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Shapingba Distrinct, Chongqing 400038, P.R. China
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27
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Fu H, Du H, Hu Z, Ying X, Zhou R. Gelsolin expression in liver, spleen and blood plasma provides insights into its function in mice following acute insults. EUR J INFLAMM 2016. [DOI: 10.1177/1721727x16678005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Background: Gelsolin (GSN) is an actin-binding plasma protein with a pivotal role in the systemic response to acute tissue damage. The present study investigated GSN expression in the liver, spleen and blood serum in mice after burn. Method: A murine model of thermal injury was selected, and the animals were sacrificed at 8, 24, 48 and 72 h after injury. Real-time quantitative polymerase chain reaction (RT-PCR) was performed to determine the messenger RNA (mRNA) expression of GSN, and GSN protein expression was determined by enzyme-linked immunosorbent assay (ELISA). Results: We found that GSN mRNA and protein were expressed in the liver, spleen and blood serum of the mice. GSN expression in these tissues was the lowest among the tested time points at 8 h after burn injury. The mortality within 72 h among the mice subjected to burn injury was significantly lower in those treated with GSN than in those not treated with GSN. Treatment with GSN markedly increased the GSN levels in the liver, spleen and blood serum after injury. Conclusion: These results indicated that GSN treatment may affect the outcome of thermal injury via changes in the GSN content of multiple tissues.
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Affiliation(s)
- Haiyan Fu
- PLA General Hospital, Beijing, PR China
- Intensive Care Unit, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, PR China
| | - Hongyang Du
- Department of Dermatology, Beijing Children’s Hospital, Capital Medical University, Beijing, PR China
| | - Zhansheng Hu
- Intensive Care Unit, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, PR China
| | - Xiudong Ying
- Intensive Care Unit, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, PR China
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28
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Marques CD, Diego LADS, Marcondes-Machado J, Amorim RL, Carvalho LR, Módolo NSP, Braz LG, Castiglia YMM. Serum concentrations and renal expressions of IL-1 and TNF-a early after hemorrhage in rats under the effect of glibenclamide. Acta Cir Bras 2016; 31:434-41. [PMID: 27487277 DOI: 10.1590/s0102-865020160070000002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 06/22/2016] [Indexed: 11/22/2022] Open
Abstract
PURPOSE To investigate changes in the serum concentration and renal expression of IL-1 and TNF-α cytokines in rats that received sevoflurane and glibenclamide prior to hemorrhage. METHODS Two groups of sevoflurane-anesthetized Wistar rats (n=10): G1 (control) and G2 (glibenclamide, 1 µg/g i.v.); hemorrhage of 30% blood volume (10% every 10 min), with replacement using Ringer solution, 5 ml/kg/h. Serum concentrations of IL-1 and TNF-α were studied in the first hemorrhage (T1) and 50 min later (T2), renal expression, at T2. RESULTS In serum, G1 TNF-α (pg/mL) was T1=178.6±33.5, T2=509.2±118.8 (p<0.05); IL-1 (pg/mL) was T1=148.8±31.3, T2=322.6±115.4 (p<0.05); in G2, TNF-α was T1=486.2±83.6, T2=261.8±79.5 (p<0.05); IL-1 was T1=347.0±72.0, T2= 327.3±90.9 (p>0.05). The expression of TNF-α and IL-1 in the glomerular and tubular cells was significantly higher in the G2 group. CONCLUSIONS Hemorrhage and glibenclamide elevated TNF-α and IL-1 concentrations in serum and kidneys. High levels of TNF-α already present before the hemorrhage in the glibenclamide group may have attenuated the damages found in the kidneys after the ischemia event.
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Affiliation(s)
- Christiane D'Oliveira Marques
- MSc, Postgraduate Program in Anesthesiology, Botucatu Medical School, Universidade Estadual Paulista (UNESP), Botucatu-SP, Brazil. Conception, design, intellectual and scientific content of the study
| | - Luis Antonio Dos Santos Diego
- PhD, Postgraduate Program in Anesthesiology, Botucatu Medical School, UNESP, Botucatu-SP, Brazil. Conception, design, intellectual and scientific content of the study
| | - Jussara Marcondes-Machado
- PhD, Department of Tropical Diseases, Botucatu Medical School, UNESP, Botucatu-SP, Brazil. Acquisition and interpretation of immunohistochemical data
| | - Renée Lauffer Amorim
- PhD, Department of Pathology, Botucatu Veterinary and Animal Science School, UNESP, Botucatu-SP, Brazil. Acquisition of data, histological examinations
| | - Lídia Raquel Carvalho
- PhD, Department of Biostatistics, Bioscience Institute, UNESP, Botucatu-SP, Brazil. Acquisition of data, statistical analysis
| | - Norma Sueli Pinheiro Módolo
- Full Professor, Department of Anesthesiology, Botucatu Medical School, UNESP, Botucatu-SP, Brazil. Critical revision
| | - Leandro Gobbo Braz
- PhD, Department of Anesthesiology, Botucatu Medical School, UNESP, Botucatu-SP, Brazil. Critical revision
| | - Yara Marcondes Machado Castiglia
- Full Professor, Department of Anesthesiology, Botucatu Medical School, UNESP, Botucatu-SP, Brazil. Manuscript writing, supervised all phases of the study
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29
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Inoue K, Suzuki T, Igarashi T, Minamishima S, Seki H, Kosugi S, Katori N, Morisaki H. Deep anesthesia worsens outcome of rats with inflammatory responses. Inflamm Res 2016; 65:563-71. [PMID: 27001561 DOI: 10.1007/s00011-016-0940-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/10/2016] [Accepted: 03/10/2016] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE We tested the hypothesis that deep anesthesia with sevoflurane, known as a potent immunomodulator, for 4 h would worsen the 24-h outcomes of rats through modulation of the inflammatory responses. METHODS Forty-nine male Wistar rats, administered low dose of lipopolysaccharide (0.5 mg/kg) intravenously to elicit moderate inflammatory responses mimicked mild surgical stress, underwent one minimum alveolar concentration (MAC) or 2 MAC sevoflurane anesthesia for 4 h. The 24-h survival rate, arterial blood gases, plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations, and rate of T lymphocyte apoptosis in spleen were evaluated. We further examined the effects of hypotension and TNF-α discharge on the survival rate. RESULTS The survival rate in 2 MAC group was significantly lower accompanied with decreased base excess and increased level of cytokines (IL-6, TNF-α) compared to 1 MAC group. The apoptosis rate did not differ between the two groups. Neither norepinephrine infusion to restore hypotension nor administration of anti-TNF-α antibody improved the outcome in the 2 MAC group. CONCLUSIONS Deep anesthesia with sevoflurane even for a short-term period augments the release of inflammatory cytokines evoked by inflammatory insults like surgical stress, impairs the acid-base balance, and subsequently deteriorates the outcomes.
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Affiliation(s)
- Kei Inoue
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Takeshi Suzuki
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Toru Igarashi
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shizuka Minamishima
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroyuki Seki
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Shizuko Kosugi
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Nobuyuki Katori
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroshi Morisaki
- Department of Anesthesiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
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30
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ShockOmics: multiscale approach to the identification of molecular biomarkers in acute heart failure induced by shock. Scand J Trauma Resusc Emerg Med 2016; 24:9. [PMID: 26822963 PMCID: PMC4730667 DOI: 10.1186/s13049-016-0197-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Accepted: 01/07/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The ShockOmics study (ClinicalTrials.gov identifier NCT02141607) is a multicenter prospective observational trial aimed at identifying new biomarkers of acute heart failure in circulatory shock, by means of a multiscale analysis of blood samples and hemodynamic data from subjects with circulatory shock. METHODS AND DESIGN Ninety septic shock and cardiogenic shock patients will be recruited in three intensive care units (ICU) (Hôpital Erasme, Université Libre de Bruxelles, Belgium; Hospital Universitari Mutua Terrassa, Spain; Hôpitaux Universitaires de Genève, Switzerland). Hemodynamic signals will be recorded every day for up to seven days from shock diagnosis (time T0). Clinical data and blood samples will be collected for analysis at: i) T1 < 16 h from T0; ii) T2 = 48 h after T0; iii) T3 = day 7 or before discharge or before discontinuation of therapy in case of fatal outcome; iv) T4 = day 100. The inclusion criteria are: shock, Sequential Organ Failure Assessment (SOFA) score > 5 and lactate levels ≥ 2 mmol/L. The exclusion criteria are: expected death within 24 h since ICU admission; > 4 units of red blood cells or >1 fresh frozen plasma transfused; active hematological malignancy; metastatic cancer; chronic immunodepression; pre-existing end stage renal disease requiring renal replacement therapy; recent cardiac surgery; Child-Pugh C cirrhosis; terminal illness. Enrollment will be preceded by the signature of the Informed Consent by the patient or his/her relatives and by the physician in charge. Three non-shock control groups will be included in the study: a) healthy blood donors (n = 5); b) septic patients (n = 10); c) acute myocardial infarction or patients with prolonged acute arrhythmia (n = 10). The hemodynamic data will be downloaded from the ICU monitors by means of dedicated software. The blood samples will be utilized for transcriptomics, proteomics and metabolomics ("-omics") analyses. DISCUSSION ShockOmics will provide new insights into the pathophysiological mechanisms underlying shock as well as new biomarkers for the timely diagnosis of cardiac dysfunction in shock and quantitative indices for assisting the therapeutic management of shock patients.
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He W, Zhou P, Chang Z, Liu B, Liu X, Wang Y, Li Y, Alam HB. Inhibition of peptidylarginine deiminase attenuates inflammation and improves survival in a rat model of hemorrhagic shock. J Surg Res 2015; 200:610-8. [PMID: 26434505 DOI: 10.1016/j.jss.2015.09.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 08/25/2015] [Accepted: 09/03/2015] [Indexed: 11/15/2022]
Abstract
BACKGROUND We have recently shown that inhibition of peptidylarginine deiminase (PAD) improves survival in a rodent model of lethal cecal ligation and puncture. The roles of PAD inhibitors in hemorrhagic shock (HS), however, are largely unknown. The goal of this study was to investigate the effects of YW3-56, a novel PAD inhibitor, on survival after severe HS. METHODS Mouse macrophages were exposed to hypoxic conditions followed by reoxygenation in the presence or absence of YW3-56. Enzyme-linked immunosorbent assay (ELISA) was performed to measure levels of secreted tumor necrosis factor α and interleukin-6 in the culture medium. Cell viability was determined by methyl thiazolyl tetrazolium assay. In the survival experiment, anesthetized male Wistar-Kyoto rats (n = 10/group) were subjected to 55% blood loss, and treated with or without YW3-56 (10 mg/kg, intraperitoneally). Survival was monitored for 12 h. In the nonsurvival experiment, morphologic changes of the lungs were examined. Levels of circulating cytokine-induced neutrophil chemoattractant 1 (CINC-1) and myeloperoxidase (MPO) in the lungs were measured by ELISA. Expression of lung intercellular adhesion molecules-1 (ICAM-1) was also determined by Western blotting. RESULTS Hypoxia/reoxygenation (H/R) insult induced tumor necrosis factor α and interleukin-6 secretion from macrophages, which was significantly attenuated by YW3-56 treatment. YW3-56 treatment also increased cell viability when macrophages were exposed to H/R up to 6/15 h and improved survival rate from 20% to 60% in lethal HS rat model. Compared to the sham groups, pulmonary MPO activity and ICAM-1 expression in the HS group were significantly increased, and acute lung injury was associated with a higher degree of CINC-1 levels in serum. Intraperitoneal delivery of YW3-56 significantly reduced pulmonary MPO and ICAM-1 expression and attenuated acute lung injury. CONCLUSIONS Our results demonstrate for the first time that administration of YW3-56, a novel PAD inhibitor, can improve survival in a rat model of HS and in a cell culture model of H/R. The survival advantage is associated with an attenuation of local and systemic pro-inflammatory cytokines and the protection against acute lung injury after hemorrhage. Thus, PAD inhibition may represent a novel and promising therapeutic strategy for severe HS.
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Affiliation(s)
- Wei He
- Department of Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Peter Zhou
- Department of Surgery, University of Michigan, Ann Arbor, Michigan; Harvard University, Cambridge, Massachusetts
| | - Zhigang Chang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan; Department of Surgical ICU, Beijing Hospital Ministry of Health, Beijing, China
| | - Baoling Liu
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Xuefeng Liu
- Department of Systems Leadership and Effectiveness Science, University of Michigan School of Nursing, Ann Arbor, Michigan
| | - Yanming Wang
- Department of Biochemistry and Molecular Biology, Pennsylvania State University, Pennsylvania
| | - Yongqing Li
- Department of Surgery, University of Michigan, Ann Arbor, Michigan
| | - Hasan B Alam
- Department of Surgery, University of Michigan, Ann Arbor, Michigan.
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Active Negative Pressure Peritoneal Therapy After Abbreviated Laparotomy: The Intraperitoneal Vacuum Randomized Controlled Trial. Ann Surg 2015; 262:38-46. [PMID: 25536308 PMCID: PMC4463030 DOI: 10.1097/sla.0000000000001095] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Supplemental Digital Content is Available in the Text. This randomized trial observed a survival difference between patients randomized to the ABThera versus Barker's vacuum pack after abbreviated laparotomy. As this difference did not seem to be mediated by improved peritoneal fluid drainage, fascial closure rates, or markers of systemic inflammation, it should be confirmed by a multicenter trial. Objective: To determine whether active negative pressure peritoneal therapy with the ABThera temporary abdominal closure device reduces systemic inflammation after abbreviated laparotomy. Background: Excessive systemic inflammation after abdominal injury or intra-abdominal sepsis is associated with poor outcomes. Methods: We conducted a single-center, randomized controlled trial. Forty-five adults with abdominal injury (46.7%) or intra-abdominal sepsis (52.3%) were randomly allocated to the ABThera (n = 23) or Barker's vacuum pack (n = 22). On study days 1, 2, 3, 7, and 28, blood and peritoneal fluid were collected. The primary endpoint was the difference in the plasma concentration of interleukin-6 (IL-6) 24 and 48 hours after temporary abdominal closure application. Results: There was a significantly lower peritoneal fluid drainage from the ABThera at 48 hours after randomization. Despite this, there was no difference in plasma concentration of IL-6 at baseline versus 24 (P = 0.52) or 48 hours (P = 0.82) between the groups. There was also no significant intergroup difference in the plasma concentrations of IL-1β, −8, −10, or −12 p70 or tumor necrosis factor α between these time points. The cumulative incidence of primary fascial closure at 90 days was similar between groups (hazard ratio, 1.6; 95% confidence interval, 0.82–3.0; P = 0.17). However, 90-day mortality was improved in the ABThera group (hazard ratio, 0.32; 95% confidence interval, 0.11–0.93; P = 0.04). Conclusions: This trial observed a survival difference between patients randomized to the ABThera versus Barker's vacuum pack that did not seem to be mediated by an improvement in peritoneal fluid drainage, fascial closure rates, or markers of systemic inflammation. Trial Registration: ClinicalTrials.gov identifier NCT01355094.
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Hsing CH, Wang JJ. Clinical implication of perioperative inflammatory cytokine alteration. ACTA ACUST UNITED AC 2015; 53:23-8. [PMID: 25837846 DOI: 10.1016/j.aat.2015.03.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 03/06/2015] [Indexed: 12/22/2022]
Abstract
Cytokines are key modulators of inflammatory responses, and play an important role in the defense and repair mechanisms following trauma. After traumatic injury, an immuno-inflammatory response is initiated immediately, and cytokines rapidly appear and function as a regulator of immunity. In pathologic conditions, imbalanced cytokines may provide systemic inflammatory responses or immunosuppression. Expression of perioperative cytokines vary by different intensities of surgical trauma and types of anesthesia and anesthetic agents. Inflammatory cytokines play important roles in postoperative organ dysfunction including central nervous system, cardiovascular, lung, liver, and kidney injury. Inhibition of cytokines could protect against traumatic injury in some circumstances, therefore cytokine inhibitors or antagonists might have the potential for reducing postoperative tissue/organ dysfunction. Cytokines are also involved in wound healing and post-traumatic pain. Application of cytokines for the improvement of surgical wound healing has been reported. Anesthesia-related immune response adjustment might reduce perioperative morbidity because it reduces proinflammatory cytokine expression; however, the overall effects of anesthetics on postoperative immune-inflammatory responses needs to be further investigated.
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Affiliation(s)
- Chung-Hsi Hsing
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan; Department of Anesthesiology, Taipei Medical University, Taipei, Taiwan.
| | - Jhi-Joung Wang
- Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan; Department of Anesthesiology, Chi-Mei Medical Center, Tainan, Taiwan
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Liu S, Cao Y, Zeng Z. The ideal target blood pressure for resuscitation during uncontrolled haemorrhagic shock. Injury 2014; 45:2110-1. [PMID: 24810667 DOI: 10.1016/j.injury.2014.04.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Accepted: 04/06/2014] [Indexed: 02/05/2023]
Affiliation(s)
- Shiping Liu
- Emergency Department, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Yu Cao
- Emergency Department, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Zhi Zeng
- Emergency Department, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
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The antimicrobial peptide lysozyme is induced after multiple trauma. Mediators Inflamm 2014; 2014:303106. [PMID: 25258475 DOI: 10.1155/2014/303106] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/21/2014] [Accepted: 08/04/2014] [Indexed: 11/17/2022] Open
Abstract
The antimicrobial peptide lysozyme is an important factor of innate immunity and exerts high potential of antibacterial activity. In the present study we evaluated the lysozyme expression in serum of multiple injured patients and subsequently analyzed their possible sources and signaling pathways. Expression of lysozyme was examined in blood samples of multiple trauma patients from the day of trauma until 14 days after trauma by ELISA. To investigate major sources of lysozyme, its expression and regulation in serum samples, different blood cells, and tissue samples were analysed by ELISA and real-time PCR. Neutrophils and hepatocytes were stimulated with cytokines and supernatant of Staphylococcus aureus. The present study demonstrates the induction and release of lysozyme in serum of multiple injured patients. The highest lysozyme expression of all tested cells and tissues was detected in neutrophils. Stimulation with trauma-related factors such as interleukin-6 and S. aureus induced lysozyme expression. Liver tissue samples of patients without trauma show little lysozyme expression compared to neutrophils. After stimulation with bacterial fragments, lysozyme expression of hepatocytes is upregulated significantly. Toll-like receptor 2, a classic receptor of Gram-positive bacterial protein, was detected as a possible target for lysozyme induction.
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Tsai CH, Yeh CH, Sheen-Chen SM, Huang CY, Liu YW, Huang CC, Shen SC, Tang RP. The kinetic expression of lipopolysaccharide-binding protein and CD14 gene in obstructive jaundice. J INVEST SURG 2014; 28:18-23. [PMID: 25093541 DOI: 10.3109/08941939.2014.943858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Binding lipopolysaccharide (LPS) with high-affinity, lipopolysaccharide-binding protein (LBP) and CD14 lower the threshold stimulatory concentrations of LPS dramatically and enhance the rate of cytokine production markedly. This study aimed to investigate the kinetic expression of LBP/CD14 and its possible relationship with tumor necrosis factor alpha (TNF-α) to better understand the pathophysiology of obstructive jaundice. MATERIALS AND METHODS The tissues (liver, spleen, intestine, and lung) of male Sprague-Dawley rats were harvested at pre-bile duct ligation in controls and at specific time points (24, 48, 72, 96, and 120 hr) after bile duct ligation. LBP, CD14, and TNF-α mRNA expression were measured in tissues harvested from controls and at the specific time points. RESULTS Hepatic LBP mRNA expression increased significantly at five days after bile duct ligation. CD 14 mRNA expression increased significantly after five days of bile duct ligation in liver, lung, spleen, and ileum. TNF-α mRNA expression increased significantly in all four organs (liver, lung, spleen, and ileum) after four days of bile duct ligation. CONCLUSION Five days of bile duct ligation upregulated CD 14 mRNA expression in liver, lung, spleen, and ileum and increased TNF-α mRNA expression simultaneously in the liver, lung, spleen, and ileum. In addition, five days of bile duct ligation also upregulated LBP mRNA expression in the liver and increased hepatic TNF-α mRNA expression simultaneously. The kinetic expressions of LBP and CD 14 in obstructive jaundice are intriguing and further evaluation is warranted.
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Affiliation(s)
- Ching-Hua Tsai
- 1Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taiwan
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Zhao L, Luo L, Chen J, Xiao J, Jia W, Xiao Y. Utilization of Extracorporeal Membrane Oxygenation Alleviates Intestinal Ischemia–Reperfusion Injury in Prolonged Hemorrhagic Shock Animal Model. Cell Biochem Biophys 2014; 70:1733-40. [DOI: 10.1007/s12013-014-0121-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
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Lin X, Zhang S, Huang R, Tan S, Liang S, Wu X, Zhuo L, Huang Q. Protective effect of tormentic acid from Potentilla chinensis against lipopolysaccharide/d-galactosamine induced fulminant hepatic failure in mice. Int Immunopharmacol 2014; 19:365-72. [DOI: 10.1016/j.intimp.2014.02.009] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2013] [Revised: 01/27/2014] [Accepted: 02/09/2014] [Indexed: 12/21/2022]
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Jellestad L, Fink T, Pradarutti S, Kubulus D, Wolf B, Bauer I, Thiemermann C, Rensing H. Inhibition of glycogen synthase kinase (GSK)-3-β improves liver microcirculation and hepatocellular function after hemorrhagic shock. Eur J Pharmacol 2014; 724:175-84. [PMID: 24389157 DOI: 10.1016/j.ejphar.2013.12.029] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 12/17/2013] [Accepted: 12/18/2013] [Indexed: 10/25/2022]
Abstract
Ischemia and reperfusion may cause liver injury and are characterized by hepatic microperfusion failure and a decreased hepatocellular function. Inhibition of glycogen synthase kinase (GSK)-3β, a serine-threonine kinase that has recently emerged as a key regulator in the modulation of the inflammatory response after stress events, may be protective in conditions like sepsis, inflammation and shock. Therefore, aim of the study was to assess the role of GSK-3β in liver microcirculation and hepatocellular function after hemorrhagic shock and resuscitation (H/R). Anesthetized male Sprague-Dawley rats underwent pretreatment with Ringer´s solution, vehicle (DMSO) or TDZD-8 (1 mg/kg), a selective GSK-3β inhibitor, 30 min before induction of hemorrhagic shock (mean arterial pressure 35±5 mmHg for 90 min) and were resuscitated with shed blood and Ringer´s solution (2h). 5h after resuscitation hepatic microcirculation was assessed by intravital microscopy. Propidium iodide (PI) positive cells, liver enzymes and alpha-GST were measured as indicators of hepatic injury. Liver function was estimated by assessment of indocyanine green plasma disappearance rate. H/R led to a significant decrease in sinusoidal diameters and impairment of liver function compared to sham operation. Furthermore, the number of PI positive cells in the liver as well as serum activities of liver enzymes and alpha-GST increased significantly after H/R. Pretreatment with TDZD-8 prevented the changes in liver microcirculation, hepatocellular injury and liver function after H/R. A significant rise in the plasma level of IL-10 was observed. Thus, inhibition of GSK-3β before hemorrhagic shock modulates the inflammatory response and improves hepatic microcirculation and hepatocellular function.
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Affiliation(s)
- Lena Jellestad
- Department of Anesthesiology, Critical Care and Pain Medicine, University of Saarland, Kirrberger Straße 1, D-66421 Homburg, Germany
| | - Tobias Fink
- Department of Anesthesiology, Critical Care and Pain Medicine, University of Saarland, Kirrberger Straße 1, D-66421 Homburg, Germany
| | - Sascha Pradarutti
- Department of Anesthesiology, Critical Care and Pain Medicine, University of Saarland, Kirrberger Straße 1, D-66421 Homburg, Germany
| | - Darius Kubulus
- Department of Anesthesiology, Critical Care and Pain Medicine, University of Saarland, Kirrberger Straße 1, D-66421 Homburg, Germany
| | - Beate Wolf
- Department of Anesthesiology, Critical Care and Pain Medicine, University of Saarland, Kirrberger Straße 1, D-66421 Homburg, Germany
| | - Inge Bauer
- Department of Anesthesiology, University Hospital Duesseldorf, Moorenstraße 5, D-40225 Duesseldorf, Germany
| | - Chris Thiemermann
- St. Bartholomew's and Royal London, School of Medicine and Dentistry, William Harvey Research Institute, Centre for Experimental Medicine, Nephrology and Critical Care, Charterhouse Square, London EC1M 6BQ, UK
| | - Hauke Rensing
- Department of Anesthesiology and Critical Care Medicine, Leopoldina Hospital, Gustav-Adolf-Straße 6-8, D-97422 Schweinfurt, Germany.
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The cardioprotective effect of hypertonic saline is associated with inhibitory effect on macrophage migration inhibitory factor in sepsis. BIOMED RESEARCH INTERNATIONAL 2013; 2013:201614. [PMID: 24371817 PMCID: PMC3858963 DOI: 10.1155/2013/201614] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Accepted: 11/08/2013] [Indexed: 01/24/2023]
Abstract
Sepsis can cause myocardial dysfunction, which contributes to the high mortality of sepsis. Hypertonic saline (HS) has been reported to increase myocardial contractility in sepsis. In the present study, mechanisms of action of HS resuscitation (4 mL of 7.5% NaCl per kilogram) on cardiac function have been evaluated in septic rats. HS was administered 1 h after LPS (10 mg/kg, i.v.) challenge. The mean arterial blood pressure significantly decreased 4 h after LPS challenge, and septic shock was observed at the end of experiment (6 h). Posttreatment with HS prevented hypotension caused by LPS and significantly improved cardiac function, evidenced by increases in left ventricular developed pressure, mean +dP/dt and -dP/dt. The amplitude of electrical-stimulated intracellular Ca(2+) transient in isolated single cardiomyocytes was significantly reduced after 6 h LPS insult, which was recovered by HS. In addition, LPS resulted in significant increases in neutrophil myeloperoxidase activity, macrophage migration inhibitory factor (MIF), and NF-κB phospho-p65 protein levels in myocardium at 6 h, which were significantly attenuated by HS. In conclusion, HS improved myocardial contractility and prevented circulatory failure induced by endotoxemia, which may attribute to improvement of intracellular calcium handling process and inhibitory effects on neutrophil infiltration and MIF production in hearts.
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Luan YY, Dong N, Xie M, Xiao XZ, Yao YM. The significance and regulatory mechanisms of innate immune cells in the development of sepsis. J Interferon Cytokine Res 2013; 34:2-15. [PMID: 24006870 DOI: 10.1089/jir.2013.0042] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Sepsis with subsequent multiple organ dysfunction is a pronounced systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. The survival rate of severe sepsis and septic shock has not markedly improved in recent decades despite a great number of receptors and molecules involved in its pathogenesis have been found and taken as therapeutic targets. It is essential to thoroughly understand the host cell-mediated immunity involved in the development of sepsis and sepsis-related organ injury. Recent studies indicate that innate immune cells (such as neutrophils, macrophages, dendritic cells, T lymphocytes, regulatory T cells, and natural killer T cells) play pivotal roles in the maintenance of peripheral homeostasis and regulation of immune responses during sepsis. Therefore, an understanding of the biological significance and pathophysiological roles of different cell populations might gain novel insights into the immunoregulatory mechanisms of sepsis. In this review, we focus on major immune cells that may play potential roles in the contribution of new therapeutic approaches for sepsis.
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Affiliation(s)
- Ying-Yi Luan
- 1 Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital , Beijing, People's Republic of China
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Zhang JL, Fei SJ, Qin X, Ye HH, Liu HX, Dai XJ, Zhang YM. Propofol inhibits hypoxia/reoxygenation-induced human gastric epithelial cell injury by suppressing the Toll-like receptor 4 pathway. Kaohsiung J Med Sci 2013; 29:289-98. [PMID: 23684133 DOI: 10.1016/j.kjms.2012.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 07/12/2012] [Indexed: 01/04/2023] Open
Abstract
This study aimed to investigate the role of the Toll-like receptor 4 (TLR4) pathway in normal human gastric epithelial (GES-1) cells under hypoxia/reoxygenation (H/R) in vitro, and the effect of propofol on injured GES-1 cells as well as its possible mechanism. Before H/R induction, GES-1 cells were preconditioned with fat emulsion, propofol, or epigallocatechin gallate. Then cell viability, cell apoptosis, and related molecules in the cells were analyzed under experimental conditions. We found that propofol 50 μmol/L markedly inhibited the H/R injury under hypoxia 1.5 h/reoxygenation 2 hours by promoting GES-1 cell viability and decreasing cell apoptosis. The TLR4 signal may be involved in the protective effect of propofol against H/R injury. The malondialdehyde contents and superoxide dismutase activities were recovered under propofol preconditioning. In summary, propofol preconditioning may exert a protective effect on H/R injury in GES-1 cells and the mechanism may be via inhibition of the activated TLR4 signal under H/R conditions.
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Affiliation(s)
- Jiao-Li Zhang
- Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou, China
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Haouzi P, Van de Louw A. Uncoupling mitochondrial activity maintains body [Formula: see text] during hemorrhage-induced O2 deficit in the anesthetized rat. Respir Physiol Neurobiol 2013; 186:87-94. [PMID: 23333818 DOI: 10.1016/j.resp.2012.12.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Revised: 12/20/2012] [Accepted: 12/21/2012] [Indexed: 01/25/2023]
Abstract
During a hemorrhagic shock (HS), O2 uptake ( [Formula: see text] ) decreases as soon as the rate of O2 delivery ( [Formula: see text] ) drops below a "critical level", a response accounted for by the reduction in mitochondrial O2supply. In urethane-anesthetized rats, [Formula: see text] was decreased within 20min from 21.5 to 2.8mlmin(-1) by slowly withdrawing 18mlkg(-1) of blood. This led to a reduction in [Formula: see text] from 6.1 to 2.4mlmin(-1) (n=5, p<0.01). Decoupling mitochondrial oxidative activity by injecting 2,4-DNP (6mgkg(-1), iv) before HS elevated [Formula: see text] to 11.9±1.2mlmin(-1) (n=6, p<0.01), which remained above control HS values throughout most of the hemorrhage. This was associated with higher levels of O2 extraction, cardiac output and ventilation than in control HS. [Formula: see text] relationship was shifted upward and to the left following DNP. In conclusion, cellular and systemic mechanisms, decreasing O2demand, account for a large part of HS induced [Formula: see text] decline resulting in an additional reduction in [Formula: see text] .
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Affiliation(s)
- Philippe Haouzi
- Pennsylvania State University, College of Medicine, Division of Pulmonary and Critical Care Medicine, Penn State Hershey Medical Center, Hershey, PA, United States.
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Dalle Lucca JJ, Li Y, Simovic MO, Slack JL, Cap A, Falabella MJ, Dubick M, Lebeda F, Tsokos GC. Decay-accelerating factor limits hemorrhage-instigated tissue injury and improves resuscitation clinical parameters. J Surg Res 2012; 179:153-67. [PMID: 23122671 DOI: 10.1016/j.jss.2012.10.017] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Revised: 10/03/2012] [Accepted: 10/11/2012] [Indexed: 11/16/2022]
Abstract
BACKGROUND Complement is invariably activated during trauma and contributes to tissue injury. Recombinant human decay-accelerating factor (DAF), a complement regulatory protein that inhibits both classical and alternative pathways, improves survival and reduces tissue damage in animal models of tissue injury. The extent to which DAF may facilitate resuscitation in hemorrhaged large animals is not known. METHODS Male Yorkshire swine assigned to one of six groups were subjected to controlled, isobaric hemorrhage over 15 min to a target mean arterial pressure (MAP) of 35 mm Hg. Hypotension was maintained for 20 min followed by a bolus intravenous injection of DAF or vehicle followed by Hextend resuscitation. Animals were observed for 3 h after hypotensive Hextend resuscitation. Survival, blood chemistry, and physiological parameters were recorded. Additionally, tissue from lung, small intestine, liver, and kidney were subjected to histopathologic evaluation and tissue deposition of complement proteins was determined by immunohistochemistry, dot-blot, and Western blot analyses. RESULTS Administration of DAF (25 μg/kg) to animals subjected to hemorrhage prior to Hextend infusion significantly improved survival (73% versus 27%); protected gut, lung, liver, and kidney tissue from damage; and resulted in reduced resuscitation fluid requirements when compared with animals subjected to hemorrhage and resuscitation with Hextend alone. Animals treated with a higher dose of DAF (50 μg/kg) followed by Hextend fluid resuscitation did not experience the same benefit, suggesting a narrow therapeutic range for use of DAF as adjunct to Hextend fluid. CONCLUSION DAF improved survival and reduced early Hextend fluid resuscitation requirements in swine subjected to hemorrhagic shock. These benefits are attributed to decreased complement deposition and limited organ damage.
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Affiliation(s)
- Jurandir J Dalle Lucca
- Immunomodulation of Trauma Program, US Army Institute of Surgical Research, San Antonio, Texas, USA.
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Van de Louw A, Haouzi P. Oxygen deficit and H2S in hemorrhagic shock in rats. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2012; 16:R178. [PMID: 23031430 PMCID: PMC3682279 DOI: 10.1186/cc11661] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 10/02/2012] [Indexed: 12/25/2022]
Abstract
Introduction Hemorrhagic shock induced O2 deficit triggers inflammation and multiple organ failure (MOF). Endogenous H2S has been proposed to be involved in MOF since plasma H2S concentration appears to increase in various types of shocks and to predict mortality. We tested the hypothesis that H2S increases during hemorrhagic shock associated with O2 deficit, and that enhancing H2S oxidation by hydroxocobalamin could reduce inflammation, O2 deficit or mortality. Methods We used a urethane anesthetized rat model, where 25 ml/kg of blood was withdrawn over 30 minutes. O2 deficit, lactic acid, tumor necrosis factor (TNF)-alpha and H2S plasma concentrations (Siegel method) were measured before and after the bleeding protocol in control animals and animals that received 140 mg/kg of hydroxocobalamin. The ability to oxidize exogenous H2S of the plasma and supernatants of the kidney and heart homogenates was determined in vitro. Results We found that withdrawing 25 ml/kg of blood led to an average oxygen deficit of 122 ± 23 ml/kg. This O2 deficit was correlated with an increase in the blood lactic acid concentration and mortality. However, the low level of absorbance of the plasma at 670 nm (A670), after adding N, N-Dimethyl-p-phenylenediamine, that is, the method used for H2S determination in previous studies, did not reflect the presence of H2S, but was a marker of plasma turbidity. There was no difference in plasmatic A670 before and after the bleeding protocol, despite the large oxygen deficit. The plasma sampled at the end of bleeding maintained a very large ability to oxidize exogenous H2S (high μM), as did the homogenates of hearts and kidneys harvested just after death. Hydroxocobalamin concentrations increased in the blood in the μM range in the vitamin B12 group, and enhanced the ability of plasma and kidneys to oxidize H2S. Yet, the survival rate, O2 deficit, H2S plasma concentration, blood lactic acid and TNF-alpha levels were not different from the control group. Conclusions In the presence of a large O2 deficit, H2S did not increase in the blood in a rat model of untreated hemorrhagic shock. Hydroxocobalamin, while effective against H2S in vitro, did not affect the hemodynamic profile or outcome in our model.
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Ding N, Dahlke K, Janze AK, Mailer PC, Maus R, Bohling J, Welte T, Bauer M, Riedemann NC, Maus UA. Role of p38 mitogen-activated protein kinase in posttraumatic immunosuppression in mice. J Trauma Acute Care Surg 2012; 73:861-8. [DOI: 10.1097/ta.0b013e31825ab11f] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Leise B, Watts M, Tanhoff E, Johnson P, Black S, Belknap J. Laminar Regulation of STAT1 and STAT3 in Black Walnut Extract and Carbohydrate Overload Induced Models of Laminitis. J Vet Intern Med 2012; 26:996-1004. [DOI: 10.1111/j.1939-1676.2012.00944.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Affiliation(s)
| | - M. Watts
- Department of Veterinary Clinical Sciences; College of Veterinary Medicine; The Ohio State University; Columbus; OH
| | - E. Tanhoff
- Department of Veterinary Clinical Sciences; College of Veterinary Medicine; The Ohio State University; Columbus; OH
| | - P.J. Johnson
- Department of Veterinary Medicine and Surgery; The University of Missouri-Columbia; Columbia; MO
| | - S.J. Black
- Department of Veterinary and Animal Sciences; University of Massachusetts; Amherst; MA
| | - J.K. Belknap
- Department of Veterinary Clinical Sciences; College of Veterinary Medicine; The Ohio State University; Columbus; OH
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Luan YY, Yao YM, Sheng ZY. Update on the immunological pathway of negative regulation in acute insults and sepsis. J Interferon Cytokine Res 2012; 32:288-98. [PMID: 22509978 PMCID: PMC3390969 DOI: 10.1089/jir.2011.0117] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Accepted: 01/16/2012] [Indexed: 12/20/2022] Open
Abstract
Sepsis with subsequent multiple organ dysfunction is a distinctly systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. In the initial stage of sepsis, a phase of immune activation can be evident, but a marked apoptosis-induced depletion of lymphocytes and a nonspecific anergy of immune function after severe trauma and burns might be responsible for the increased susceptibility of the host to subsequent septic complications. Recent studies indicated that negative regulation of immune function plays a pivotal role in the maintenance of peripheral homeostasis and regulation of immune responses; therefore, an understanding of the basic pathways might give rise to novel insights into the mechanisms of sepsis and immune homeostasis. This review is an attempt to provide a summary of the different pathways of negative regulation that are involved in the pathogenesis of sepsis, secondary to acute insults.
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Affiliation(s)
- Ying-yi Luan
- Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, People's Republic of China
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Danger signals activating the immune response after trauma. Mediators Inflamm 2012; 2012:315941. [PMID: 22778496 PMCID: PMC3388465 DOI: 10.1155/2012/315941] [Citation(s) in RCA: 148] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Revised: 03/23/2012] [Accepted: 03/26/2012] [Indexed: 12/29/2022] Open
Abstract
Sterile injury can cause a systemic inflammatory response syndrome (SIRS) that resembles the host response during sepsis. The inflammatory response following trauma comprises various systems of the human body which are cross-linked with each other within a highly complex network of inflammation. Endogenous danger signals (danger-associated molecular patterns; DAMPs; alarmins) as well as exogenous pathogen-associated molecular patterns (PAMPs) play a crucial role in the initiation of the immune response. With popularization of the “danger theory,” numerous DAMPs and PAMPs and their corresponding pathogen-recognition receptors have been identified. In this paper, we highlight the role of the DAMPs high-mobility group box protein 1 (HMGB1), interleukin-1α (IL-1α), and interleukin-33 (IL-33) as unique dual-function mediators as well as mitochondrial danger signals released upon cellular trauma and necrosis.
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