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1
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Zhou K, Qin Q, Lu J. Pathophysiological mechanisms of ARDS: a narrative review from molecular to organ-level perspectives. Respir Res 2025; 26:54. [PMID: 39948645 PMCID: PMC11827456 DOI: 10.1186/s12931-025-03137-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) remains a life-threatening pulmonary condition with persistently high mortality rates despite significant advancements in supportive care. Its complex pathophysiology involves an intricate interplay of molecular and cellular processes, including cytokine storms, oxidative stress, programmed cell death, and disruption of the alveolar-capillary barrier. These mechanisms drive localized lung injury and contribute to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Unlike prior reviews that primarily focus on isolated mechanisms, this narrative review synthesizes the key pathophysiological processes of ARDS across molecular, cellular, tissue, and organ levels. MAIN BODY By integrating classical theories with recent research advancements, we provide a comprehensive analysis of how inflammatory mediators, metabolic reprogramming, oxidative stress, and immune dysregulation synergistically drive ARDS onset and progression. Furthermore, we critically evaluate current evidence-based therapeutic strategies, such as lung-protective ventilation and prone positioning, while exploring innovative therapies, including stem cell therapy, gene therapy, and immunotherapy. We emphasize the significance of ARDS subtypes and their inherent heterogeneity in guiding the development of personalized treatment strategies. CONCLUSIONS This narrative review provides fresh perspectives for future research, ultimately enhancing patient outcomes and optimizing management approaches in ARDS.
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Affiliation(s)
- Kaihuan Zhou
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, China
| | - Qianqian Qin
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, China
| | - Junyu Lu
- Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, China.
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2
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Liao Y, Zhang W, Zhou M, Zhu C, Zou Z. Ubiquitination in pyroptosis pathway: A potential therapeutic target for sepsis. Cytokine Growth Factor Rev 2024; 80:72-86. [PMID: 39294049 DOI: 10.1016/j.cytogfr.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 09/03/2024] [Indexed: 09/20/2024]
Abstract
Sepsis remains a significant clinical challenge, causing numerous deaths annually and representing a major global health burden. Pyroptosis, a unique form of programmed cell death characterized by cell lysis and the release of inflammatory mediators, is a crucial factor in the pathogenesis and progression of sepsis, septic shock, and organ dysfunction. Ubiquitination, a key post-translational modification influencing protein fate, has emerged as a promising target for managing various inflammatory conditions, including sepsis. This review integrates the current knowledge on sepsis, pyroptosis, and the ubiquitin system, focusing on the molecular mechanisms of ubiquitination within pyroptotic pathways activated during sepsis. By exploring how modulating ubiquitination can regulate pyroptosis and its associated inflammatory signaling pathways, this review provides insights into potential therapeutic strategies for sepsis, highlighting the need for further research into these complex molecular networks.
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Affiliation(s)
- Yan Liao
- School of Anesthesiology, Naval Medical University, Shanghai 200433, China
| | - Wangzheqi Zhang
- School of Anesthesiology, Naval Medical University, Shanghai 200433, China
| | - Miao Zhou
- Department of Anesthesiology, the Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University, Nanjing, Jiangsu 210009, China
| | - Chenglong Zhu
- School of Anesthesiology, Naval Medical University, Shanghai 200433, China.
| | - Zui Zou
- School of Anesthesiology, Naval Medical University, Shanghai 200433, China.
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3
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Wang Y, Shi Y, Shao Y, Lu X, Zhang H, Miao C. S100A8/A9 hi neutrophils induce mitochondrial dysfunction and PANoptosis in endothelial cells via mitochondrial complex I deficiency during sepsis. Cell Death Dis 2024; 15:462. [PMID: 38942784 PMCID: PMC11213914 DOI: 10.1038/s41419-024-06849-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 06/16/2024] [Accepted: 06/19/2024] [Indexed: 06/30/2024]
Abstract
S100a8/a9, largely released by polymorphonuclear neutrophils (PMNs), belongs to the S100 family of calcium-binding proteins and plays a role in a variety of inflammatory diseases. Although S100a8/a9 has been reported to trigger endothelial cell apoptosis, the mechanisms of S100a8/a9-induced endothelial dysfunction during sepsis require in-depth research. We demonstrate that high expression levels of S100a8/a9 suppress Ndufa3 expression in mitochondrial complex I via downregulation of Nrf1 expression. Mitochondrial complex I deficiency contributes to NAD+-dependent Sirt1 suppression, which induces mitochondrial disorders, including excessive fission and blocked mitophagy, and mtDNA released from damaged mitochondria ultimately activates ZBP1-mediated PANoptosis in endothelial cells. Moreover, based on comprehensive scRNA-seq and bulk RNA-seq analyses, S100A8/A9hi neutrophils are closely associated with the circulating endothelial cell count (a useful marker of endothelial damage), and S100A8 is an independent risk factor for poor prognosis in sepsis patients.
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Affiliation(s)
- Yanghanzhao Wang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuxin Shi
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuwen Shao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xihua Lu
- Department of Anesthesiology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Hao Zhang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China.
- Shanghai Key Laboratory of Perioperative Stress and Protection, Shanghai, China.
- Department of Anesthesiology, Shanghai Medical College, Fudan University, Shanghai, China.
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4
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Zhao L, Su F, Zhang N, Wu H, Shen Y, Liu H, Li X, Li Y, Xie K. The impact of the new acute respiratory distress syndrome (ARDS) criteria on Berlin criteria ARDS patients: a multicenter cohort study. BMC Med 2023; 21:456. [PMID: 37996902 PMCID: PMC10666384 DOI: 10.1186/s12916-023-03144-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/31/2023] [Indexed: 11/25/2023] Open
Abstract
OBJECTIVE The European Society of Intensive Care Medicine (ESICM) recently recommended changes to the criteria of acute respiratory distress syndrome (ARDS), patients with high-flow oxygen were included, however, the effect of these changes remains unclear. Our objectives were to evaluate the performance of these new criteria and to compare the outcomes of patients meeting the new ARDS criteria with those meeting the Berlin ARDS criteria. METHODS This was a retrospective cohort. The patients admitted to the intensive care unit (ICU) were diagnosed with ARDS. Patients were classified as meeting Berlin criteria ARDS (n = 4279), high-flow nasal oxygen (HFNO) criteria ARDS (n = 559), or new criteria ARDS (n = 4838). RESULTS In comparison with HFNO criteria ARDS and new criteria ARDS, patients with Berlin criteria ARDS demonstrated lower blood oxygen levels assessed by PaO2/FiO2, SpO2/FiO2, and ROX (SpO2/FiO2/respiratory rate) (p < 0.001); and higher severity of illness assessed by the Sequential Organ Failure Assessment (SOFA) score, Acute Physiology And Chronic Health Evaluations (APACHE II), Simplified Acute Physiology Score (SAPS II) (p < 0.001), (p < 0.001), and longer ICU and hospital stays (p < 0.001). In comparison with the HFNO criteria, patients meeting Berlin criteria ARDS had higher hospital mortality (10.6% vs. 16.9%; p = 0.0082), 28-day mortality (10.6% vs. 16.5%; p = 0.0079), and 90-day mortality (10.7% vs. 17.1%; p = 0.0083). ARDS patients with HFNO did not have severe ARDS; Berlin criteria ARDS patients with severe ARDS had the highest mortality rate (approximately 33%). PaO2/FiO2, SpO2/FiO2, and ROX negatively correlated with the SOFA and APACHE II scores. The SOFA and APACHE II scores had high specificity and sensitivity for prognosis in patients with new criteria ARDS. CONCLUSION The new criteria of ARDS reduced the severity of illness, length of stay in the ICU, length of hospital stays, and overall mortality. SOFA and APACHE II scores remain important in assessing the prognosis of patients with new criteria ARDS. TRIAL REGISTRATION Registration number: ChiCTR2200067084.
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Affiliation(s)
- Lina Zhao
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Fuhong Su
- Experimental Laboratory of Intensive Care, Université Libre de Bruxelles, 1000, Brussels, Belgium
| | - Nannan Zhang
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Hening Wu
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yuehao Shen
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Haiying Liu
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xuguang Li
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yun Li
- Department of Anesthesiology, Tianjin Institute of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
| | - Keliang Xie
- Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin, 300052, China.
- Department of Anesthesiology, Tianjin Institute of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, 300052, China.
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Yang B, Wang X, Liu Z, Lu Z, Fang G, Xue X, Luo T. Endothelial-Related Biomarkers in Evaluation of Vascular Function During Progression of Sepsis After Severe Trauma: New Potential Diagnostic Tools in Sepsis. J Inflamm Res 2023; 16:2773-2782. [PMID: 37435113 PMCID: PMC10332413 DOI: 10.2147/jir.s418697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 07/03/2023] [Indexed: 07/13/2023] Open
Abstract
Purpose This study aimed to investigate the changes in endothelial-related biomarkers and their relationship with the incidence and prognosis of patients with sepsis after severe trauma. Methods A total of 37 severe trauma patients admitted to our hospital from Jan. to Dec. 2020 were enrolled in our research. All enrolled patients were divided into the sepsis and the non-sepsis groups. Endothelial progenitor cells (EPCs), circulating endothelial cells (CECs), and endothelial microparticles (EMPs) were detected on admission time; 24-48 hours and 48-72 hours after admission respectively. Demographic data, Acute Physiology, Chronic Health Evaluation (APACHE) II, and Sequential Organ Failure Assessment (SOFA) score were calculated every 24 h of admission to assess the severity of organ dysfunction. Receiver operating characteristic (ROC) curves were drawn to compare the areas under the curve (AUC) of endothelial-related biomarkers for the diagnosis of sepsis. Results The incidence rate of sepsis was 45.95% in all patients. The SOFA score in the sepsis group was significantly higher than that in the non-sepsis group (2 points vs 0 points, P<0.01). The number of EPCs, CECs, and EMPs all rose quickly in the early phase after trauma. The number of EPCs was similar in both groups, but the number of CECs and EMPs in the Sepsis Group was much higher than in the non-Sepsis Group (all P<0.01). Logistic regression analysis showed that the occurrence of sepsis was closely related to the expression of 0-24h CECs and 0-24h EMPs. The AUC ROC for CECs in different time periods were 0.815, 0.877, and 0.882, respectively (all P<0.001). The AUC ROC for EMPs in 0-24h was 0.868 (P=0.005). Conclusion The expression of EMPs was higher in early severe trauma, and high levels of EMPs were significantly higher in patients with early sepsis and poor prognosis.
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Affiliation(s)
- Biao Yang
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Xiaoyong Wang
- Department of Gastrointestinal Surgery, People’s Hospital of Haimen City, Nantong, Jiangsu Province, 226100, People’s Republic of China
| | - Zhaorui Liu
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Zhengmao Lu
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Guoen Fang
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Xuchao Xue
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
| | - Tianhang Luo
- Department of General Surgery, Changhai Hospital, The Second Military Medical University, Shanghai, 200433, People’s Republic of China
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Costa Monteiro AC, Matthay MA. Are circulating endothelial cells the next target for transcriptome-level pathway analysis in ARDS? Am J Physiol Lung Cell Mol Physiol 2023; 324:L393-L399. [PMID: 36749906 PMCID: PMC10110698 DOI: 10.1152/ajplung.00353.2022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) has had no mortality-improving pharmacological intervention despite 50 years of high-caliber research due to its heterogeneity (Huppert LA, Matthay MA, Ware LB. Semin Respir Crit Care Med 40: 31-39, 2019). For the field to advance, better definitions for ARDS subgroups that more uniformly respond to therapies are needed (Bos LDJ, Scicluna BP, Ong DSY, Cremer O, van der Poll T, Schultz MJ. Am J Respir Crit Care Med 200: 42-50, 2019; Dickson RP, Schultz MJ, T van der P, Schouten LR, Falkowski NR, Luth JE, Sjoding MW, Brown CA, Chanderraj R, Huffnagle GB, Bos LDJ, Biomarker Analysis in Septic ICU Patients (BASIC) Consortium. Am J Respir Crit Care Med 201: 555-563, 2020; Sinha P, Calfee CS. Am J Respir Crit Care Med 200: 4-6, 2019; Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, NHLBI ARDS Network. Lancet Respir Med 2: 611-620, 2014; Hendrickson CM, Matthay MA. Pulm Circ 8: 1-12, 2018). A plethora of high-quality clinical research has uncovered the next generation of soluble biomarkers that provide the predictive enrichment necessary for trial recruitment; however, plasma-soluble markers do not specify the damaged organ of origin nor do they provide insight into disease mechanisms. In this perspective, we make the case for querying the transcriptome of circulating endothelial cells (CECs), which when shed from vessels after inflammatory insult, become heralds of site-specific inflammatory damage. We review the application of CEC quantification to multiple disease phenotypes (including myocardial infarction, vasculitides, cancer, and ARDS), in each case supporting the association of CEC number with disease severity. We also argue for the utility of single-cell RNA transcriptomics to the understanding of cell-specific contributions to disease pathophysiology and its potential to uncover novel insight on signals contributing to CEC shedding in ARDS.
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Affiliation(s)
- Ana C Costa Monteiro
- Department of Medicine, Division of Pulmonary and Critical Care, University of California, Los Angeles, California, United States
| | - Michael A Matthay
- Cardiovascular Research Institute, Department of Medicine and Anesthesia, University of California, San Francisco, California, United States
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Bhandari M, Singh RK, Laishevtcev A, Mohapatra TM, Nigam M, Mori E, Vasconcelos de Lacerda BCG, Coutinho HDM, Mishra AP. Revisiting scrub typhus: A neglected tropical disease. Comp Immunol Microbiol Infect Dis 2022; 90-91:101888. [PMID: 36252451 DOI: 10.1016/j.cimid.2022.101888] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/18/2022] [Accepted: 09/29/2022] [Indexed: 02/08/2023]
Abstract
Scrub typhus is an under diagnosed re-emerging vector borne disease caused by an intracellular gram negative bacteria, Orientia. The disease is commonly prevalent in rural and hilly areas of Tsutsugumashi triangle. The diagnosis of the disease is very challenging due to similarity of its early symptoms with other febrile illnesses, like dengue and COVID 19, as well as non-availability of rapid, reliable and cost-effective methods. Moreover, the diverse clinical presentation in severe cases make it significant health problem. The occupational and behavioral risks responsible for the transmission lead to urgent need of vaccine development against the disease. The complete knowledge about its pathogenesis and the interaction with host's immune cells may help the scientists in developing the appropriate diagnostic methods as well as the vaccines.
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Affiliation(s)
- Munni Bhandari
- Department of Microbiology, School of Life Sciences, Hemvati Nandan Bahuguna Garhwal University, Srinagar (Garhwal) 246174, India.
| | - Rahul Kunwar Singh
- Department of Microbiology, School of Life Sciences, Hemvati Nandan Bahuguna Garhwal University, Srinagar (Garhwal) 246174, India.
| | - Alexey Laishevtcev
- Federal Research Center - All-Russian Scientific Research Institute of Experimental Veterinary Medicine named after K.I. Skryabin and Y.R. Kovalenko of the Russian Academy of Sciences, Moscow, Russia; Laboratory of Biocontrol and Antimicrobial Resistance, Orel State, University Named After I.S. Turgenev, Orel, Russia.
| | - Tribhuvan Mohan Mohapatra
- Department of Microbiology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India.
| | - Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, Srinagar Garhwal-246174, Uttarakhand, India.
| | - Edna Mori
- CECAPE - College of Dentistry, Av. Padre Cícero, 3917, Juazeiro do Norte, São José CE 63024-015, Brazil.
| | | | | | - Abhay Prakash Mishra
- Department of Pharmacology, Faculty of Health Science, University of Free State, Bloemfontein 9300, South Africa.
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Combes A, Brodie D, Aissaoui N, Bein T, Capellier G, Dalton HJ, Diehl JL, Kluge S, McAuley DF, Schmidt M, Slutsky AS, Jaber S. Extracorporeal carbon dioxide removal for acute respiratory failure: a review of potential indications, clinical practice and open research questions. Intensive Care Med 2022; 48:1308-1321. [PMID: 35943569 DOI: 10.1007/s00134-022-06796-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/20/2022] [Indexed: 02/04/2023]
Abstract
Extracorporeal carbon dioxide removal (ECCO2R) is a form of extracorporeal life support (ECLS) largely aimed at removing carbon dioxide in patients with acute hypoxemic or acute hypercapnic respiratory failure, so as to minimize respiratory acidosis, allowing more lung protective ventilatory settings which should decrease ventilator-induced lung injury. ECCO2R is increasingly being used despite the lack of high-quality evidence, while complications associated with the technique remain an issue of concern. This review explains the physiological basis underlying the use of ECCO2R, reviews the evidence regarding indications and contraindications, patient management and complications, and addresses organizational and ethical considerations. The indications and the risk-to-benefit ratio of this technique should now be carefully evaluated using structured national or international registries and large randomized trials.
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Affiliation(s)
- Alain Combes
- Sorbonne Université INSERM Unité Mixte de Recherche (UMRS) 1166, Institute of Cardiometabolism and Nutrition, Paris, France. .,Service de Médecine Intensive-Réanimation, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, INSERM, UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition, 47, boulevard de l'Hôpital, 75013, Paris, France.
| | - Daniel Brodie
- Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, NewYork-Presbyterian Hospital, New York, USA.,Center for Acute Respiratory Failure, NewYork-Presbyterian Hospital, New York, USA
| | - Nadia Aissaoui
- Assistance publique des hopitaux de Paris (APHP), Cochin Hospital, Intensive Care Medicine, Université de Paris and Paris Cardiovascular Research Center, INSERM U970, Paris, France
| | - Thomas Bein
- Faculty of Medicine, University of Regensburg, Regensburg, Germany
| | - Gilles Capellier
- CHU Besançon, Réanimation Médicale, 2500, Besançon, France.,Université de Franche Comte, EA, 3920, Besançon, France.,Department of Epidemiology and Preventive Medicine, Australian and New Zealand Intensive, Care Research Centre, Monash University, Melbourne, Australia
| | - Heidi J Dalton
- Heart and Vascular Institute and Department of Pediatrics, INOVA Fairfax Medical Center, Falls Church, VA, USA
| | - Jean-Luc Diehl
- Medical Intensive Care Unit and Biosurgical Research Lab (Carpentier Foundation), HEGP Hospital, Assistance Publique-Hôpitaux de Paris-Centre (APHP-Centre), Paris, France.,Université de Paris, INSERM, Innovative Therapies in Haemostasis, 75006, Paris, France
| | - Stefan Kluge
- Department of Intensive Care, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Daniel F McAuley
- Belfast Health and Social Care Trust, Royal Victoria Hospital, Belfast, UK.,Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | - Matthieu Schmidt
- Sorbonne Université INSERM Unité Mixte de Recherche (UMRS) 1166, Institute of Cardiometabolism and Nutrition, Paris, France.,Service de Médecine Intensive-Réanimation, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, INSERM, UMRS_1166-ICAN, Institute of Cardiometabolism and Nutrition, 47, boulevard de l'Hôpital, 75013, Paris, France
| | - Arthur S Slutsky
- Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.,Keenan Centre for Biomedical Research, Li Ka Shing Knowledge Institute, St Michael's Hospital, Unity Health Toronto, Toronto, ON, Canada
| | - Samir Jaber
- PhyMedExp, University of Montpellier, Institut National de La Santé Et de La Recherche Médicale (INSERM), Centre National de La Recherche Scientifique (CNRS), Centre Hospitalier Universitaire (CHU) Montpellier, Montpellier, France.,Département d'Anesthésie-Réanimation, Hôpital Saint-Eloi, Montpellier Cedex, France
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9
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Meng S, Kang K, Fei D, Yang S, Pan S, Yu K, Zhao M. MiR-363-3p/S1PR1 axis inhibits sepsis-induced acute lung injury via the inactivation of NF-κB signaling. Exp Anim 2022; 71:305-315. [PMID: 35173110 PMCID: PMC9388337 DOI: 10.1538/expanim.21-0160] [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] [Indexed: 11/04/2022] Open
Abstract
Infection-associated inflammation and coagulation are critical pathologies in sepsis-induced acute lung injury (ALI). This study aimed to investigate the effects of microRNA-363-3p (miR-363-3p) on sepsis-induced ALI and explore the underlying mechanisms. A cecal ligation and puncture-induced septic mouse model was established. The results of this study suggested that miR-363-3p was highly expressed in lung tissues of septic mice. Knockdown of miR-363-3p attenuated sepsis-induced histopathological damage, the inflammation response and oxidative stress in lung tissues. Furthermore, knockdown of miR-363-3p reduced the formation of platelet-derived microparticles and thrombin generation in blood samples of septic mice. Downregulation of miR-363-3p suppressed sphingosine-1-phosphate receptor 1 (S1PR1) expression in lung tissues and subsequently inactivated the nuclear factor kappa-B ligand (NF-κB) signaling. A luciferase reporter assay confirmed that miR-363-3p directly targeted the 3'-UTR of the mouse S1pr1 mRNA. Collectively, our study suggests that inactivation of NF-κB signaling is involved in the miR-363-3p/S1PR1 axis-mediated protective effect on septic ALI.
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Affiliation(s)
- Shishuai Meng
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University
| | - Kai Kang
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University
| | - Dongsheng Fei
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University
| | - Songlin Yang
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University
| | - Shangha Pan
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University
| | - Kaijiang Yu
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University.,The Cell Transplantation Key Laboratory of National Health Commission
| | - Mingyan Zhao
- Department of Intensive Care Unit, The First Affiliated Hospital of Harbin Medical University
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10
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Peng M, Yan QH, Gao Y, Zhang Z, Zhang Y, Wang YF, Wu HN. Correlation between circulating endothelial cell level and acute respiratory distress syndrome in postoperative patients. World J Clin Cases 2021; 9:9731-9740. [PMID: 34877312 PMCID: PMC8610911 DOI: 10.12998/wjcc.v9.i32.9731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/27/2021] [Accepted: 09/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is injury of alveolar epithelial cells and capillary endothelial cells caused by various factors, including endogenous and exogenous lung factors, leading to diffuse pulmonary interstitial and alveolar edema, and acute respiratory failure. ARDS involves alveolar epithelial cells and pulmonary interstitial capillary endothelial cells. Circulating endothelial cells (CECs) are the only marker that directly reflects vascular endothelial injury in vivo. There have been few studies on the correlation between peripheral blood CECs and ARDS at home and abroad. The lungs are the organs with the highest capillary density and the most endothelial cells, thus, it is speculated that when ARDS occurs, CECs are stimulated and damaged, and released into the circulatory system.
AIM To explore the correlation between CEC level and severity of ARDS in patients postoperatively.
METHODS Blood samples were collected from all patients on day 2 (d2) and day 5 (d5) after surgery. The control group comprised 32 healthy volunteers. Number of CECs was measured by flow cytometry, and operation time was recorded. Changes in various indexes of patients were monitored, and diagnosis of ARDS was determined based on ARDS Berlin definition. We comprised d2 CECs in different groups, correlation between operation time and d2 CECs, ARDS of different severity by d2 CECs, and predictive value of d2 CECs for ARDS in postoperative patients.
RESULTS The number of d2 CECs in the ARDS group was significantly higher than that in the healthy control group (P < 0.001). The number of d2 CECs in the ARDS group was significantly higher than that in the non-ARDS group (P < 0.001). The number of d2 CECs in the non-ARDS group was significantly higher than that in the healthy control group (P < 0.001). Operation time was positively correlated with number of CECs on d2 (rs = 0.302, P = 0.001). The number of d2 CECs in the deceased group was significantly higher than that in the improved group (P < 0.001). There was no significant difference in number of d2 CECs between patients with mild and moderate ARDS. The number of d2 CECs in patients with severe ARDS was significantly higher than that in patients with mild and moderate ARDS (P = 0.041, P = 0.037). There was no significant difference in number of d5 and d2 CECs in the non-ARDS group after admission to intensive care. The number of d5 CECs was higher than the number of d2 CECs in the ARDS improved group (P < 0.001). The number of d5 CECs was higher than the number of d2 CECs in the ARDS deceased group (P = 0.002). If the number of CECs was > 1351/mL, sensitivity and specificity of predicting ARDS were 80.8% and 78.1%, respectively.
CONCLUSION Changes in number of CECs might predict occurrence and adverse outcome of ARDS after surgery, and higher numbers of CECs indicate worse prognosis of ARDS.
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Affiliation(s)
- Min Peng
- Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Qing-He Yan
- Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Ying Gao
- Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Zhen Zhang
- Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Ying Zhang
- Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - Yi-Feng Wang
- Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin 300070, China
| | - He-Ning Wu
- Department of Intensive Care Unit, Tianjin Medical University General Hospital, Tianjin 300070, China
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11
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Pioselli B, Salomone F, Mazzola G, Amidani D, Sgarbi E, Amadei F, Murgia X, Catinella S, Villetti G, De Luca D, Carnielli V, Civelli M. Pulmonary surfactant: a unique biomaterial with life-saving therapeutic applications. Curr Med Chem 2021; 29:526-590. [PMID: 34525915 DOI: 10.2174/0929867328666210825110421] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/26/2021] [Accepted: 06/29/2021] [Indexed: 11/22/2022]
Abstract
Pulmonary surfactant is a complex lipoprotein mixture secreted into the alveolar lumen by type 2 pneumocytes, which is composed by tens of different lipids (approximately 90% of its entire mass) and surfactant proteins (approximately 10% of the mass). It is crucially involved in maintaining lung homeostasis by reducing the values of alveolar liquid surface tension close to zero at end-expiration, thereby avoiding the alveolar collapse, and assembling a chemical and physical barrier against inhaled pathogens. A deficient amount of surfactant or its functional inactivation is directly linked to a wide range of lung pathologies, including the neonatal respiratory distress syndrome. This paper reviews the main biophysical concepts of surfactant activity and its inactivation mechanisms, and describes the past, present and future roles of surfactant replacement therapy, focusing on the exogenous surfactant preparations marketed worldwide and new formulations under development. The closing section describes the pulmonary surfactant in the context of drug delivery. Thanks to its peculiar composition, biocompatibility, and alveolar spreading capability, the surfactant may work not only as a shuttle to the branched anatomy of the lung for other drugs but also as a modulator for their release, opening to innovative therapeutic avenues for the treatment of several respiratory diseases.
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Affiliation(s)
| | | | | | | | - Elisa Sgarbi
- Preclinical R&D, Chiesi Farmaceutici, Parma. Italy
| | | | - Xabi Murgia
- Department of Biotechnology, GAIKER Technology Centre, Zamudio. Spain
| | | | | | - Daniele De Luca
- Division of Pediatrics and Neonatal Critical Care, Antoine Béclère Medical Center, APHP, South Paris University Hospitals, Paris, France; Physiopathology and Therapeutic Innovation Unit-U999, South Paris-Saclay University, Paris. France
| | - Virgilio Carnielli
- Division of Neonatology, G Salesi Women and Children's Hospital, Polytechnical University of Marche, Ancona. Italy
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12
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Melkumyants A, Buryachkovskaya L, Lomakin N, Antonova O, Serebruany V. Mild COVID-19 and Impaired Blood Cell-Endothelial Crosstalk: Considering Long-Term Use of Antithrombotics? Thromb Haemost 2021; 122:123-130. [PMID: 34482535 DOI: 10.1055/a-1551-9911] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Current coronavirus disease 2019 (COVID-19) pandemic reveals thrombotic, vascular, and endothelial dysfunctions at peak disease. However, the duration, degree of damage, and appropriate long-term use of antithrombotic strategies are unclear. Most COVID data are yielded from random clinical observations or autopsy of postmortem samples, while precise blood cellular data in survivors are insufficient. METHODS We analyzed erythrocytes, circulating endothelial cells, and echinocytes by electron microscopy and flow cytometry in patients with confirmed COVID-19 (n = 31) and matched healthy controls (n = 32) on admission and at hospital discharge. RESULTS All patients experienced mild disease, none required pulmonary support, and all survived. Admission number of circulating endothelial cells was significantly (40-100 times) higher in COVID-19 patients. Cells were massively damaged by multiple fenestrae in membranes with diameter comparable to the size of supercapsid in SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus. COVID-19 also provoked formation of stacked aggregated erythrocytes capable of clogging microvascular bed and of diminishing oxygen supply. In some patients, such abnormalities persisted at hospital discharge revealing remaining intracellular penetration of SARS-CoV-2 where it may be replicated and returned to circulation. CONCLUSION These observational and descriptive data suggest that persistent viral cell injury may cause blood vessel damage; their increased permeability resulted in tissue edema, inflammation, platelet activation, and augmented thrombosis. There is a residual blood cell damage following the acute phase in some COVID-19 survivors. Controlled outcome-driven trials are urgently needed for exploring optimal use of long-term antithrombotics and vascular protection strategies even after mild COVID-19.
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Affiliation(s)
- Arthur Melkumyants
- Cell Adhesion Department, National Medical Research Center of Cardiology, Moscow, Russia.,Department of Physics of Living Systems, Institute of Physics and Technology, Moscow, Russia
| | | | - Nikita Lomakin
- Cardiology Division, Central Clinical Hospital of Presidential Administration, Moscow, Russia
| | - Olga Antonova
- Cell Adhesion Department, National Medical Research Center of Cardiology, Moscow, Russia
| | - Victor Serebruany
- Division of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
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13
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De Luca D, Cogo P, Kneyber MC, Biban P, Semple MG, Perez-Gil J, Conti G, Tissieres P, Rimensberger PC. Surfactant therapies for pediatric and neonatal ARDS: ESPNIC expert consensus opinion for future research steps. Crit Care 2021; 25:75. [PMID: 33618742 PMCID: PMC7898495 DOI: 10.1186/s13054-021-03489-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 02/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pediatric (PARDS) and neonatal (NARDS) acute respiratory distress syndrome have different age-specific characteristics and definitions. Trials on surfactant for ARDS in children and neonates have been performed well before the PARDS and NARDS definitions and yielded conflicting results. This is mainly due to heterogeneity in study design reflecting historic lack of pathobiology knowledge. We reviewed the available clinical and preclinical data to create an expert consensus aiming to inform future research steps and advance the knowledge in this area. Eight trials investigated the use of surfactant for ARDS in children and ten in neonates, respectively. There were improvements in oxygenation (7/8 trials in children, 7/10 in neonates) and mortality (3/8 trials in children, 1/10 in neonates) improved. Trials were heterogeneous for patients' characteristics, surfactant type and administration strategy. Key pathobiological concepts were missed in study design. Consensus with strong agreement was reached on four statements: 1. There are sufficient preclinical and clinical data to support targeted research on surfactant therapies for PARDS and NARDS. Studies should be performed according to the currently available definitions and considering recent pathobiology knowledge. 2. PARDS and NARDS should be considered as syndromes and should be pre-clinically studied according to key characteristics, such as direct or indirect (primary or secondary) nature, clinical severity, infectious or non-infectious origin or patients' age. 3. Explanatory should be preferred over pragmatic design for future trials on PARDS and NARDS. 4. Different clinical outcomes need to be chosen for PARDS and NARDS, according to the trial phase and design, trigger type, severity class and/or surfactant treatment policy. We advocate for further well-designed preclinical and clinical studies to investigate the use of surfactant for PARDS and NARDS following these principles.
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Affiliation(s)
- Daniele De Luca
- Division of Pediatrics and Neonatal Critical Care, "A.Béclère" Medical Centre, Paris Saclay University Hospitals, APHP, 157 Rue de la Porte de Trivaux, 92140, Clamart (Paris-IDF), France.
- Physiopathology and Therapeutic Innovation Unit-INSERM U999, Paris Saclay University, Paris, France.
| | - Paola Cogo
- Department of Pediatrics, University of Udine, Udine, Italy
| | - Martin C Kneyber
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Beatrix Children's Hospital Groningen, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
- Critical Care, Anesthesiology, Peri-Operative and Emergency Medicine (CAPE), University of Groningen, Groningen, The Netherlands
| | - Paolo Biban
- Department of Neonatal and Pediatric Critical Care, Azienda Ospedaliera Universitaria Integrata Verona, Verona, Italy
| | - Malcolm Grace Semple
- Health Protection Research Unit in Emerging and Zoonotic Infections, Department of Clinical Infection, Microbiology and Immunology, University of Liverpool, Liverpool, UK
| | - Jesus Perez-Gil
- Department of Biochemistry and Molecular Biology and Research Institute "Hospital 12 de Octubre", Complutense University, Madrid, Spain
| | - Giorgio Conti
- Department of Anesthesiology and Intensive Care, Catholic University of the Sacred Heart, Rome, Italy
| | - Pierre Tissieres
- Division of Pediatric Critical Care and Neonatal Medicine, "Kremlin-Bicetre" Medical Center, Paris Saclay University Hospitals, APHP, Paris, France
- Integrative Cellular Biology Institute-UMR 9198, Host-Pathogen Interactions Team, Paris Saclay University, Paris, France
| | - Peter C Rimensberger
- Division of Neonatology and Pediatric Critical Care, Department of Pediatrics, University Hospital of Geneva, University of Geneva, Geneva, Switzerland
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14
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Peng F, Liang C, Chang W, Sun Q, Xie J, Qiu H, Yang Y. Prognostic Significance of Plasma Hepatocyte Growth Factor in Sepsis. J Intensive Care Med 2021; 37:352-358. [PMID: 33611982 DOI: 10.1177/0885066621993423] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND To assess any correlation of plasma hepatocyte growth factor (HGF) levels with relevant endothelial cell injury parameters and determine the prognostic value in septic patients. METHODS A prospective, observational study was conducted in patients with sepsis admitted to the Department of Critical Care Medicine at the Zhongda Hospital from November 2017 to March 2018. Plasma HGF levels were measured by enzyme-linked immunosorbent assay in the first 24 h after admission (day 1) and on day 3. The primary endpoint was defined as all-cause 28-day mortality. Furthermore, we analyzed the correlation of HGF with relevant endothelial cell injury markers. RESULTS Eighty-six patients admitted with sepsis were included. HGF levels of nonsurvivors were elevated compared to those of survivors on day 1 (1940.62 ± 74.66 pg/mL vs. 1635.61 ± 47.49 pg/mL; P = 0.002) and day 3 (1824.82 ± 137.52 pg/mL vs. 1309.77 ± 83.49 pg/mL; P = 0.001) and showed a strong correlation with von Willebrand factor (r = 0.45, P < 0.0001), lactate (r = 0.35, P = 0.0011), pulmonary vascular permeability index (r = 0.38, P = 0.0241), first 24 h fluid administration (r = 0.38, P < 0.0001), and sequential organ failure assessment score (r = 0.40, P = 0.0001). Plasma HGF levels were able to prognostically discriminate between survivors and nonsurvivors on day 1 (AUC: 0.72, 95%CI: 0.60-0.84) and day 3 (AUC: 0.77, 95%CI: 0.63-0.91). CONCLUSIONS HGF levels are associated with sepsis and correlated with established markers of endothelial cell injury. Elevated HGF levels in sepsis patients are an efficient indicator of poor prognosis. TRIAL REGISTRATION The study was registered in Clinical Trial (Registration Number: NCT02883231).
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Affiliation(s)
- Fei Peng
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Chenglong Liang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Wei Chang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Qin Sun
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Jianfeng Xie
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Haibo Qiu
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Yi Yang
- Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
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15
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Nizzoli ME, Merati G, Tenore A, Picone C, Consensi E, Perotti L, Ferretti VV, Sambo M, Di Sabatino A, Iotti GA, Arcaini L, Bruno R, Belliato M. Circulating endothelial cells in COVID-19. Am J Hematol 2020; 95:E187-E188. [PMID: 32491212 PMCID: PMC7300913 DOI: 10.1002/ajh.25881] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 05/23/2020] [Indexed: 02/05/2023]
Affiliation(s)
| | - Gabriele Merati
- Department of Molecular MedicineUniversity of Pavia Pavia Italy
| | - Annamaria Tenore
- Division of HematologyFondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Cristina Picone
- Division of HematologyFondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Erica Consensi
- Division of HematologyFondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Luciano Perotti
- Department of Intensive MedicineFondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Virginia V. Ferretti
- Biometry and Clinical Epidemiology ServiceFondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Margherita Sambo
- Department of Clinical, Surgical, Diagnostic, and Paediatric SciencesUniversity of Pavia Pavia Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine, Fondazione IRCCS Policlinico San MatteoUniversity of Pavia Pavia Italy
| | - Giorgio A. Iotti
- Department of Intensive MedicineFondazione IRCCS Policlinico San Matteo Pavia Italy
- Department of Clinical, Surgical, Diagnostic, and Paediatric SciencesUniversity of Pavia Pavia Italy
| | - Luca Arcaini
- Department of Molecular MedicineUniversity of Pavia Pavia Italy
- Division of HematologyFondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Raffaele Bruno
- Department of Clinical, Surgical, Diagnostic, and Paediatric SciencesUniversity of Pavia Pavia Italy
- Division of Infectious Diseases IFondazione IRCCS Policlinico San Matteo Pavia Italy
| | - Mirko Belliato
- Department of Intensive MedicineFondazione IRCCS Policlinico San Matteo Pavia Italy
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16
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Diehl JL, Peron N, Chocron R, Debuc B, Guerot E, Hauw-Berlemont C, Hermann B, Augy JL, Younan R, Novara A, Langlais J, Khider L, Gendron N, Goudot G, Fagon JF, Mirault T, Smadja DM. Respiratory mechanics and gas exchanges in the early course of COVID-19 ARDS: a hypothesis-generating study. Ann Intensive Care 2020; 10:95. [PMID: 32676824 PMCID: PMC7364286 DOI: 10.1186/s13613-020-00716-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
Rationale COVID-19 ARDS could differ from typical forms of the syndrome. Objective Pulmonary microvascular injury and thrombosis are increasingly reported as constitutive features of COVID-19 respiratory failure. Our aim was to study pulmonary mechanics and gas exchanges in COVID-2019 ARDS patients studied early after initiating protective invasive mechanical ventilation, seeking after corresponding pathophysiological and biological characteristics. Methods Between March 22 and March 30, 2020 respiratory mechanics, gas exchanges, circulating endothelial cells (CEC) as markers of endothelial damage, and D-dimers were studied in 22 moderate-to-severe COVID-19 ARDS patients, 1 [1–4] day after intubation (median [IQR]). Measurements and main results Thirteen moderate and 9 severe COVID-19 ARDS patients were studied after initiation of high PEEP protective mechanical ventilation. We observed moderately decreased respiratory system compliance: 39.5 [33.1–44.7] mL/cmH2O and end-expiratory lung volume: 2100 [1721–2434] mL. Gas exchanges were characterized by hypercapnia 55 [44–62] mmHg, high physiological dead-space (VD/VT): 75 [69–85.5] % and ventilatory ratio (VR): 2.9 [2.2–3.4]. VD/VT and VR were significantly correlated: r2 = 0.24, p = 0.014. No pulmonary embolism was suspected at the time of measurements. CECs and D-dimers were elevated as compared to normal values: 24 [12–46] cells per mL and 1483 [999–2217] ng/mL, respectively. Conclusions We observed early in the course of COVID-19 ARDS high VD/VT in association with biological markers of endothelial damage and thrombosis. High VD/VT can be explained by high PEEP settings and added instrumental dead space, with a possible associated role of COVID-19-triggered pulmonary microvascular endothelial damage and microthrombotic process.
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Affiliation(s)
- J-L Diehl
- Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France. .,Intensive Care Unit and Biosurgical Research Lab (Carpentier Foundation), AH-HP, Georges Pompidou European Hospital, 20 Rue Leblanc, 75015, Paris, France.
| | - N Peron
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - R Chocron
- Université de Paris, PARCC, INSERM, 75015, Paris, France.,Emergency Department, AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - B Debuc
- Plastic Surgery Department, AP-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - E Guerot
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - C Hauw-Berlemont
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - B Hermann
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - J L Augy
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - R Younan
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - A Novara
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - J Langlais
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - L Khider
- Vascular Medicine Department and Biosurgical Research Lab (Carpentier Foundation), AP-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - N Gendron
- Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France.,Hematology Department and Biosurgical Research Lab (Carpentier Foundation), AH-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - G Goudot
- Emergency Department, AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - J-F Fagon
- Intensive Care Unit, AH-HP, Georges Pompidou European Hospital, Université de Paris, 75015, Paris, France
| | - T Mirault
- Université de Paris, PARCC, INSERM, 75015, Paris, France.,Vascular Medicine Department, AP-HP, Georges Pompidou European Hospital, 75015, Paris, France
| | - D M Smadja
- Université de Paris, Innovative Therapies in Haemostasis, INSERM, 75006, Paris, France.,Hematology Department and Biosurgical Research Lab (Carpentier Foundation), AH-HP, Georges Pompidou European Hospital, 75015, Paris, France
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17
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Xu S, Pan X, Mao L, Pan H, Xu W, Hu Y, Yu X, Chen Z, Qian S, Ye Y, Huang Y, Pan J. Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation. Cell Commun Signal 2020; 18:104. [PMID: 32641132 PMCID: PMC7341624 DOI: 10.1186/s12964-020-00603-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 05/26/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis. METHODS Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling. RESULTS Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition. CONCLUSIONS Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis. Video Abstract.
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Affiliation(s)
- Shunyao Xu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Xiaojun Pan
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Lingjie Mao
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Hao Pan
- Wenzhou Medical University, Wenzhou, Zhejiang P.R. China
| | - Wenwei Xu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Yufeng Hu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Xueshu Yu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Zhiqiang Chen
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Songzan Qian
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Yincai Ye
- Department of Blood Transfusion, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang P.R. China
| | - Yueyue Huang
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
| | - Jingye Pan
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Nanbaixiang road, Wenzhou, Zhejiang 325000 P.R. China
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18
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Marchetti M. COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure. Ann Hematol 2020; 99:1701-1707. [PMID: 32583086 PMCID: PMC7312112 DOI: 10.1007/s00277-020-04138-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 06/09/2020] [Indexed: 02/07/2023]
Abstract
COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.
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Affiliation(s)
- Monia Marchetti
- Hematology Department, Az Osp SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy.
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19
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Meduri GU, Chrousos GP. General Adaptation in Critical Illness: Glucocorticoid Receptor-alpha Master Regulator of Homeostatic Corrections. Front Endocrinol (Lausanne) 2020; 11:161. [PMID: 32390938 PMCID: PMC7189617 DOI: 10.3389/fendo.2020.00161] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/09/2020] [Indexed: 12/20/2022] Open
Abstract
In critical illness, homeostatic corrections representing the culmination of hundreds of millions of years of evolution, are modulated by the activated glucocorticoid receptor alpha (GRα) and are associated with an enormous bioenergetic and metabolic cost. Appreciation of how homeostatic corrections work and how they evolved provides a conceptual framework to understand the complex pathobiology of critical illness. Emerging literature place the activated GRα at the center of all phases of disease development and resolution, including activation and re-enforcement of innate immunity, downregulation of pro-inflammatory transcription factors, and restoration of anatomy and function. By the time critically ill patients necessitate vital organ support for survival, they have reached near exhaustion or exhaustion of neuroendocrine homeostatic compensation, cell bio-energetic and adaptation functions, and reserves of vital micronutrients. We review how critical illness-related corticosteroid insufficiency, mitochondrial dysfunction/damage, and hypovitaminosis collectively interact to accelerate an anti-homeostatic active process of natural selection. Importantly, the allostatic overload imposed by these homeostatic corrections impacts negatively on both acute and long-term morbidity and mortality. Since the bioenergetic and metabolic reserves to support homeostatic corrections are time-limited, early interventions should be directed at increasing GRα and mitochondria number and function. Present understanding of the activated GC-GRα's role in immunomodulation and disease resolution should be taken into account when re-evaluating how to administer glucocorticoid treatment and co-interventions to improve cellular responsiveness. The activated GRα interdependence with functional mitochondria and three vitamin reserves (B1, C, and D) provides a rationale for co-interventions that include prolonged glucocorticoid treatment in association with rapid correction of hypovitaminosis.
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Affiliation(s)
- Gianfranco Umberto Meduri
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, United States
- Memphis Veterans Affairs Medical Center, Memphis, TN, United States
| | - George P. Chrousos
- University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece
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20
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Li Z, Yin M, Zhang H, Ni W, Pierce RW, Zhou HJ, Min W. BMX Represses Thrombin-PAR1-Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis. Circ Res 2020; 126:471-485. [PMID: 31910739 DOI: 10.1161/circresaha.119.315769] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
RATIONALE BMX (bone marrow kinase on the X chromosome) is highly expressed in the arterial endothelium from the embryonic stage to the adult stage in mice. It is also expressed in microvessels and the lymphatics in response to pathological stimuli. However, its role in endothelial permeability and sepsis remains unknown. OBJECTIVE We aimed to delineate the function of BMX in thrombin-mediated endothelial permeability and the vascular leakage that occurs with sepsis in cecal ligation and puncture models. METHODS AND RESULTS The cecal ligation and puncture model was applied to WT (wild type) and BMX-KO (BMX global knockout) mice to induce sepsis. Meanwhile, the electric cell-substrate impedance sensing assay was used to detect transendothelial electrical resistance in vitro and, the modified Miles assay was used to evaluate vascular leakage in vivo. We showed that BMX loss caused lung injury and inflammation in early cecal ligation and puncture-induced sepsis. Disruption of BMX increased thrombin-mediated permeability in mice and cultured endothelial cells by 2- to 3-fold. The expression of BMX in macrophages, neutrophils, platelets, and lung epithelial cells was undetectable compared with that in endothelial cells, indicating that endothelium dysfunction, rather than leukocyte and platelet dysfunction, was involved in vascular permeability and sepsis. Mechanistically, biochemical and cellular analyses demonstrated that BMX specifically repressed thrombin-PAR1 (protease-activated receptor-1) signaling in endothelial cells by directly phosphorylating PAR1 and promoting its internalization and deactivation. Importantly, pretreatment with the selective PAR1 antagonist SCH79797 rescued BMX loss-mediated endothelial permeability and pulmonary leakage in early cecal ligation and puncture-induced sepsis. CONCLUSIONS Acting as a negative regulator of PAR1, BMX promotes PAR1 internalization and signal inactivation through PAR1 phosphorylation. Moreover, BMX-mediated PAR1 internalization attenuates endothelial permeability to protect vascular leakage during early sepsis.
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Affiliation(s)
- Zhao Li
- From the The Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China (Z.L.).,Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (Z.L., M.Y., H.Z., W.N., R.W.P., H.J.Z., W.M.)
| | - Mingzhu Yin
- Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (Z.L., M.Y., H.Z., W.N., R.W.P., H.J.Z., W.M.).,Department of Dermatology, Hunan Engineering Research, Center of Skin Health and Disease, Xiangya Hospital, Central South University, China (M.Y.)
| | - Haifeng Zhang
- Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (Z.L., M.Y., H.Z., W.N., R.W.P., H.J.Z., W.M.)
| | - Weiming Ni
- Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (Z.L., M.Y., H.Z., W.N., R.W.P., H.J.Z., W.M.)
| | - Richard W Pierce
- Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (Z.L., M.Y., H.Z., W.N., R.W.P., H.J.Z., W.M.)
| | - Huanjiao Jenny Zhou
- Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (Z.L., M.Y., H.Z., W.N., R.W.P., H.J.Z., W.M.)
| | - Wang Min
- Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT (Z.L., M.Y., H.Z., W.N., R.W.P., H.J.Z., W.M.)
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Trent B, Fisher J, Soong L. Scrub Typhus Pathogenesis: Innate Immune Response and Lung Injury During Orientia tsutsugamushi Infection. Front Microbiol 2019; 10:2065. [PMID: 31555249 PMCID: PMC6742975 DOI: 10.3389/fmicb.2019.02065] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 08/22/2019] [Indexed: 01/28/2023] Open
Abstract
Scrub typhus is an understudied, potentially lethal disease caused by infection with Orientia tsutsugamushi. Despite causing an estimated 1 million cases per year and an increasing global presence, mechanisms of scrub typhus pathogenesis remain unclear. One of the most life-threatening conditions that can arise in scrub typhus patients is acute respiratory distress syndrome (ARDS). The development of ARDS is a complex process; some of its pathological hallmarks, including prolonged recruitment of inflammatory immune cells to the lung and vasculature damage, have been observed in humans and/or animal models of O. tsutsugamushi infection. Although different cell types and mechanisms may contribute to ARDS development during O. tsutsugamushi infection, this review highlights our current evidence of pulmonary endothelial activation and damage, the potential roles of neutrophils and macrophages in the lung, and the knowledge gaps in this field. Continued investigation of the lung microenvironment and cellular interactions will help elucidate disease pathogenesis and possible treatment during scrub typhus.
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Affiliation(s)
- Brandon Trent
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States
| | - James Fisher
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
| | - Lynn Soong
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States.,Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
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22
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Chen M, Kong C, Zheng Z, Li Y. Identification of Biomarkers Associated with Septic Cardiomyopathy Based on Bioinformatics Analyses. J Comput Biol 2019; 27:69-80. [PMID: 31424269 DOI: 10.1089/cmb.2019.0181] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
This study intended to identify biomarkers for septic cardiomyopathy (SC). Microarray data GSE79962 including 20 SC samples and 11 normal samples were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between SC and control groups were identified, followed with functional enrichment analyses. In addition, the protein-protein interaction (PPI) network and modules were constructed. Finally, a transcription factors (TFs)-microRNA (miRNA)-target gene network was constructed and the potential drugs targeting key DEGs were searched. There were 119 upregulated and 80 downregulated genes in the SC group compared with the control group. The upregulated DEGs were significantly enriched tumor necrosis factor signaling pathway, Jak-signal transducer and activator of transcription (STAT) signaling pathway, hypoxia-inducible transcription factor-1 signaling pathway, chemokine signaling pathway, and cytokine-cytokine receptor interaction. The downregulated genes involved in biological processes of negative regulation of DNA biosynthetic process, and skeletal muscle cell differentiation. CCL2, STAT3, MYC, and SERPINE1 were hub nodes in the PPI network and modules. miR-29 family and miR-30 family were considered as key miRNAs, and TATA, MEF2, and STAT5B were considered as key TFs. SERPINE1 and MYC were also drug target genes. The identified DEGs and pathways may be implicated in the progression of human SC, which may lead to a better understanding of SC pathogenesis.
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Affiliation(s)
- Mengwei Chen
- Department of Cardiovascular and Huadong Hospital, Fudan University, Shanghai, China
| | - Chengqi Kong
- Department of Cardiovascular and Huadong Hospital, Fudan University, Shanghai, China
| | - Zhiyuan Zheng
- Department of Cardiovascular and Huadong Hospital, Fudan University, Shanghai, China
| | - Yin Li
- Department of Emergency, Huadong Hospital, Fudan University, Shanghai, China
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23
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Yang ZX, Guo DY, Wei AB, Hu CB, Yan ML, Cai GL. Effect of Human Umbilical Vein Endothelial Cells on Immune Responses of Lipopolysaccharide-Induced THP1 Macrophages. Chin Med J (Engl) 2019; 131:2226-2228. [PMID: 30203798 PMCID: PMC6144854 DOI: 10.4103/0366-6999.240795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Affiliation(s)
- Zhou-Xin Yang
- Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou, Zhejiang 310013, China
| | - Dong-Yang Guo
- Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou, Zhejiang 310013, China
| | - An-Bang Wei
- Department of Clinical Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China
| | - Cai-Bao Hu
- Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou, Zhejiang 310013, China
| | - Mo-Lei Yan
- Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou, Zhejiang 310013, China
| | - Guo-Long Cai
- Department of Critical Care Medicine, Zhejiang Hospital, Hangzhou, Zhejiang 310013, China
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Phosphatidylinositol 3-kinase-mediated HO-1/CO represses Fis1 levels and alleviates lipopolysaccharide-induced oxidative injury in alveolar macrophages. Exp Ther Med 2018; 16:2735-2742. [PMID: 30210614 DOI: 10.3892/etm.2018.6448] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 05/17/2018] [Indexed: 12/14/2022] Open
Abstract
Sepsis-related acute respiratory distress syndrome is characterized by marked oxidative stress and mitochondrial dysfunction lacking of specific therapy. Heme oxygenase (HO)-1 followed by endogenous carbon monoxide (CO) exerted a cytoprotective effect against multi-organ damage during sepsis. Additionally, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which serves as an upstream regulator of HO-1, was associated with inflammation and oxidative stress. Therefore, the purpose of the present study was to investigate whether the PI3K/Akt pathway was involved in the effects of HO-1/CO on the expression of mitochondrial fission 1 protein (Fis1). In the present study, CO releasing molecule-2 (CORM2), as the exogenous source of CO, plus LY294002, as a specific PI3K inhibitor, were pre-incubated in lipopolysaccharide (LPS)-simulated rat NR8383 alveolar macrophages. The results demonstrated that CORM2 improved cell viability, inhibited tumor necrosis factor-α levels, malondialdehyde contents, while elevating interleukin-10 levels and superoxide dismutase activities. In addition, pretreatment with CORM2 suppressed the fragmentation of mitochondria, upregulated the expressions of phosphorylated-Akt and HO-1 but downregulated the levels of Fis1 mRNA and protein in LPS-exposed cells. However, pretreatment with LY294002 significantly inhibited the phosphorylation of Akt, decreased HO-1 levels, aggravated mitochondrial fragmentation, increased Fis1 mRNA and protein levels, and reversed the above protective effects of CORM2. Collectively, the results of the present study indicated that the PI3K/Akt pathway mediated the cytoprotective effects of HO-1/CO on the transcription and translational levels of Fis1, and alleviated LPS-induced oxidative injury in alveolar macrophages.
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25
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Chen L, Li W, Qi D, Wang D. Lycium barbarum polysaccharide protects against LPS-induced ARDS by inhibiting apoptosis, oxidative stress, and inflammation in pulmonary endothelial cells. Free Radic Res 2018; 52:480-490. [PMID: 29502482 DOI: 10.1080/10715762.2018.1447105] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Lan Chen
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wen Li
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Di Qi
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Daoxin Wang
- Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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26
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Li W, Sun R, Zhou S, Ma J, Xie Y, Xu B, Long H, Luo K, Fang K. 2,3,5,4'‑Tetrahydroxystilbene‑2‑O‑β‑D‑glucoside inhibits septic serum‑induced inflammatory injury via interfering with the ROS‑MAPK‑NF‑κB signaling pathway in pulmonary aortic endothelial cells. Int J Mol Med 2017; 41:1643-1650. [PMID: 29286092 DOI: 10.3892/ijmm.2017.3329] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 11/29/2017] [Indexed: 11/06/2022] Open
Abstract
Sepsis is characterized by injury to the microvasculature and the microvascular endothelial cells, leading to barrier dysfunction. However, the specific role of injury in septic endothelial barrier dysfunction remains to be elucidated. In the present study, it was hypothesized that endothelial cell inflammatory injury is likely required for barrier dysfunction under septic conditions in vitro. 2,3,5,4'‑Tetrahydroxystilbene‑2‑O‑β‑D‑glucoside (TSG), a compound extracted from Chinese herbs, is able to inhibit the inflammatory injury of septic‑serum in endothelial cells. In the present study, cell viability was assayed by CCK‑8 method; mRNA and protein expression was identified by RT‑qPCR, western blot or Elisa, respectively and the production of reactive oxygen species was observed by a fluorescence microscope. The present study indicated that septic serum significantly decreased the cell viability of pulmonary aortic endothelial cells (PAECs) following co‑cultivation for 6 h, which occurred in a time‑dependent manner. TSG notably increased the viability of PAECs in a time‑ and concentration‑dependent manner. Further investigations revealed that septic serum increased the secretion of interleukin (IL)‑1β, IL‑6 and C‑reactive protein in PAECs, whereas pretreatment with TSG significantly decreased the secretion of these inflammatory factors. These data indicated that septic serum increased inflammatory injury to the PAECs, and TSG decreased this injury via the reactive oxygen species‑mitogen‑activated protein kinase‑nuclear factor‑κB signaling pathway.
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Affiliation(s)
- Wenqiang Li
- Intensive Care Unit, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Ruifang Sun
- Department of Joint Surgery, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Sumei Zhou
- Intensive Care Unit, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Jinluan Ma
- Intensive Care Unit, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Yingguang Xie
- Intensive Care Unit, Jining No. 1 People's Hospital, Jining, Shandong 272011, P.R. China
| | - Bingcan Xu
- Department of Emergency, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Huibao Long
- Department of Emergency, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Keqin Luo
- Department of Emergency, Sun Yat‑Sen Memorial Hospital, Sun Yat‑Sen University, Guangzhou, Guangdong 510120, P.R. China
| | - Kuaifa Fang
- Emergency of ICU, Huiyang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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27
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Orbegozo D, Rahmania L, Irazabal M, Mendoza M, Annoni F, De Backer D, Creteur J, Vincent JL. Endocan as an early biomarker of severity in patients with acute respiratory distress syndrome. Ann Intensive Care 2017; 7:93. [PMID: 28884313 PMCID: PMC5589715 DOI: 10.1186/s13613-017-0311-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 08/18/2017] [Indexed: 12/15/2022] Open
Abstract
Background Plasma concentrations of endocan, a proteoglycan preferentially expressed in the pulmonary vasculature, may represent a biomarker of lung (dys)function. We sought to determine whether the measurement of plasma endocan levels early in the course of acute respiratory distress syndrome (ARDS) could help predict risk of death or of prolonged ventilation. Methods All patients present in the department of intensive care during a 150-day period were screened for ARDS (using the Berlin definition). Endocan concentrations were measured at the moment of ARDS diagnosis (T0) and the following morning (T1). We compared data from survivors and non-survivors and data from survivors with less than 10 days of ventilator support (good evolution) and those who died or needed more than 10 days of mechanical ventilation (poor evolution). Results are presented as numbers (percentages), mean ± standard deviation or medians (percentile 25–75). Results Ninety-six consecutive patients were included [median APACHE II score of 21 (17–27) and SOFA score of 9 (6–12), PaO2/FiO2 ratio 155 (113–206)]; 64 (67%) had sepsis and 51 (53%) were receiving norepinephrine. Non-survivors were older (66 ± 15 vs. 59 ± 18 years, p = 0.045) and had higher APACHE II scores [27 (22–30) vs. 20 (15–24), p < 0.001] and blood lactate concentrations at study inclusion [2.1 (1.3–4.0) vs. 1.5 (0.9–2.6) mmol/L, p = 0.024] than survivors, but PaO2/FiO2 ratios [150 (116–207) vs. 158 (110–206), p = 0.95] were similar in the two groups. Endocan concentrations on the day after ARDS diagnosis were significantly higher in patients with poor evolution than in those with good evolution [12.0 (6.8–18.6) vs. 7.2 (5.4–12.5), p < 0.01]. Conclusion Blood endocan concentrations early in the evolution of ARDS may be a useful marker of disease severity. Electronic supplementary material The online version of this article (doi:10.1186/s13613-017-0311-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Diego Orbegozo
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Lokmane Rahmania
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Marian Irazabal
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Manuel Mendoza
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Filippo Annoni
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Daniel De Backer
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Jacques Creteur
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, 1070, Brussels, Belgium.
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28
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Zhu Z, Liang L, Zhang R, Wei Y, Su L, Tejera P, Guo Y, Wang Z, Lu Q, Baccarelli AA, Zhu X, Bajwa EK, Taylor Thompson B, Shi GP, Christiani DC. Whole blood microRNA markers are associated with acute respiratory distress syndrome. Intensive Care Med Exp 2017; 5:38. [PMID: 28856588 PMCID: PMC5577350 DOI: 10.1186/s40635-017-0155-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 08/21/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND MicroRNAs (miRNAs) can play important roles in inflammation and infection, which are common manifestations of acute respiratory distress syndrome (ARDS). We assessed if whole blood miRNAs were potential diagnostic biomarkers for human ARDS. METHODS This nested case-control study (N = 530) examined a cohort of ARDS patients and critically ill at-risk controls. Whole blood miRNA profiles and logistic regression analyses identified miRNAs correlated with ARDS. Stratification analysis also assessed selected miRNA markers for their role in sepsis and pneumonia associated with ARDS. Receiver operating characteristic (ROC) analysis evaluated miRNA diagnostic performance, along with Lung Injury Prediction Score (LIPS). RESULTS Statistical analyses were performed on 294 miRNAs, selected from 754 miRNAs after quality control screening. Logistic regression identified 22 miRNAs from a 156-patient discovery cohort as potential risk or protective markers of ARDS. Three miRNAs-miR-181a, miR-92a, and miR-424-from the discovery cohort remained significantly associated with ARDS in a 373-patient independent validation cohort (FDR q < 0.05) and meta-analysis (p < 0.001). ROC analyses demonstrated a LIPS baseline area-under-the-curve (AUC) value of ARDS of 0.708 (95% CI 0.651-0.766). Addition of miR-181a, miR-92a, and miR-424 to LIPS increased baseline AUC to 0.723 (95% CI 0.667-0.778), with a relative integrated discrimination improvement of 2.40 (p = 0.005) and a category-free net reclassification index of 27.21% (p = 0.01). CONCLUSIONS miR-181a and miR-92a are risk biomarkers for ARDS, whereas miR-424 is a protective biomarker. Addition of these miRNAs to LIPS can improve the risk estimate for ARDS.
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Affiliation(s)
- Zhaozhong Zhu
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA
| | - Liming Liang
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ruyang Zhang
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA.,Department of Environmental Health, Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yongyue Wei
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA.,Department of Environmental Health, Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory for Modern Toxicology, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Li Su
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA
| | - Paula Tejera
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA
| | - Yichen Guo
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA
| | - Zhaoxi Wang
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA
| | - Quan Lu
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA
| | - Andrea A Baccarelli
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA
| | - Xi Zhu
- Department of Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Ednan K Bajwa
- Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - B Taylor Thompson
- Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Guo-Ping Shi
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - David C Christiani
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, USA. .,Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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29
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Focus on ARDS. Intensive Care Med 2017; 43:1495-1497. [PMID: 28779224 DOI: 10.1007/s00134-017-4902-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 07/28/2017] [Indexed: 10/19/2022]
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Abstract
Sepsis affects practically all aspects of endothelial cell (EC) function and is thought to be the key factor in the progression from sepsis to organ failure. Endothelial functions affected by sepsis include vasoregulation, barrier function, inflammation, and hemostasis. These are among other mechanisms often mediated by glycocalyx shedding, such as abnormal nitric oxide metabolism, up-regulation of reactive oxygen species generation due to down-regulation of endothelial-associated antioxidant defenses, transcellular communication, proteases, exposure of adhesion molecules, and activation of tissue factor. This review covers current insight in EC-associated hemostatic responses to sepsis and the EC response to inflammation. The endothelial cell lining is highly heterogeneous between different organ systems and consequently also in its response to sepsis. In this context, we discuss the response of the endothelial cell lining to sepsis in the kidney, liver, and lung. Finally, we discuss evidence as to whether the EC response to sepsis is adaptive or maladaptive. This study is a result of an Acute Dialysis Quality Initiative XIV Sepsis Workgroup meeting held in Bogota, Columbia, between October 12 and 15, 2014.
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Orbegozo Cortés D, Rahmania L, Irazabal M, Santacruz C, Fontana V, De Backer D, Creteur J, Vincent JL. Microvascular reactivity is altered early in patients with acute respiratory distress syndrome. Respir Res 2016; 17:59. [PMID: 27188409 PMCID: PMC4869291 DOI: 10.1186/s12931-016-0375-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 05/05/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acute respiratory distress syndrome (ARDS) is associated with vascular endothelial dysfunction. The resultant microvascular reactivity can be assessed non-invasively using near-infrared spectroscopy (NIRS) and a vascular occlusion test (VOT) and changes have been correlated with severity of organ dysfunction and mortality in other critically ill populations. We used NIRS to study the presence of microcirculatory alterations in patients with ARDS. METHODS We studied 27 healthy volunteers and 32 ARDS patients admitted to our intensive care department. NIRS measurements were performed within 24 h after diagnosis (Berlin definition). VOTs were performed by inflating an arm-cuff to a pressure greater than the systolic pressure for 3 min, followed by rapid deflation. The descending (Desc) and ascending (Asc) thenar muscle oxygen saturation (StO2) slopes were calculated. We compared data from volunteers with those from ARDS patients, from ARDS survivors and non-survivors, and from ARDS survivors who required <7 days ventilatory support (good evolution) with those who required >7 days support or died (poor evolution). RESULTS ARDS patients had lower StO2 values [75(67-80) vs 79(76-81) %, p = 0.04] and Asc slopes [185(115-233) vs 258(216-306) %/min, p < 0.01] than healthy volunteers, but Desc slopes were similar. The Asc slope was lower in the patients with a poor evolution than in the other patients [121(90-209) vs 222(170-293) %/min, p < 0.01], and in the non-survivors than in the survivors [95(73-120) vs 212(165-252) %/min, p < 0.01]. CONCLUSIONS In ARDS patients, microvascular reactivity is altered early, and the changes are directly related to the severity of the disease. The ascending slope is the best determinant of outcome.
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Affiliation(s)
- Diego Orbegozo Cortés
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Lokmane Rahmania
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Marian Irazabal
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Carlos Santacruz
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Vito Fontana
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Daniel De Backer
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Jacques Creteur
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium
| | - Jean-Louis Vincent
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles, Route de Lennik 808, B-1070, Brussels, Belgium.
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ZHANG MINGHAO, WANG XIUYU, BAI BIN, ZHANG RUI, LI YUNHONG, WANG YIN. Oxymatrine protects against sepsis-induced myocardial injury via inhibition of the TNF-α/p38-MAPK/caspase-3 signaling pathway. Mol Med Rep 2016; 14:551-9. [DOI: 10.3892/mmr.2016.5250] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 02/22/2016] [Indexed: 11/06/2022] Open
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Østergaard L, Granfeldt A, Secher N, Tietze A, Iversen NK, Jensen MS, Andersen KK, Nagenthiraja K, Gutiérrez‐Lizardi P, Mouridsen K, Jespersen SN, Tønnesen EK. Microcirculatory dysfunction and tissue oxygenation in critical illness. Acta Anaesthesiol Scand 2015; 59:1246-59. [PMID: 26149711 PMCID: PMC4758388 DOI: 10.1111/aas.12581] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Revised: 05/19/2015] [Accepted: 06/14/2015] [Indexed: 12/19/2022]
Abstract
Severe sepsis is defined by organ failure, often of the kidneys, heart, and brain. It has been proposed that inadequate delivery of oxygen, or insufficient extraction of oxygen in tissue, may explain organ failure. Despite adequate maintenance of systemic oxygen delivery in septic patients, their morbidity and mortality remain high. The assumption that tissue oxygenation can be preserved by maintaining its blood supply follows from physiological models that only apply to tissue with uniformly perfused capillaries. In sepsis, the microcirculation is profoundly disturbed, and the blood supply of individual organs may therefore no longer reflect their access to oxygen. We review how capillary flow patterns affect oxygen extraction efficacy in tissue, and how the regulation of tissue blood flow must be adjusted to meet the metabolic needs of the tissue as capillary flows become disturbed as observed in critical illness. Using the brain, heart, and kidney as examples, we discuss whether disturbed capillary flow patterns might explain the apparent mismatch between organ blood flow and organ function in sepsis. Finally, we discuss diagnostic means of detecting capillary flow disturbance in animal models and in critically ill patients, and address therapeutic strategies that might improve tissue oxygenation by modifying capillary flow patterns.
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Affiliation(s)
- L. Østergaard
- Department of Neuroradiology Aarhus University Hospital Aarhus Denmark
- Center of Functionally Integrative Neuroscience and MINDLab Aarhus University Aarhus Denmark
| | - A. Granfeldt
- Department of Anaesthesia and Intensive Care Medicine Aarhus University Hospital Aarhus Denmark
| | - N. Secher
- Department of Anaesthesia and Intensive Care Medicine Aarhus University Hospital Aarhus Denmark
| | - A. Tietze
- Department of Neuroradiology Aarhus University Hospital Aarhus Denmark
- Center of Functionally Integrative Neuroscience and MINDLab Aarhus University Aarhus Denmark
| | - N. K. Iversen
- Center of Functionally Integrative Neuroscience and MINDLab Aarhus University Aarhus Denmark
| | - M. S. Jensen
- Center of Functionally Integrative Neuroscience and MINDLab Aarhus University Aarhus Denmark
| | - K. K. Andersen
- Department of Anaesthesia and Intensive Care Medicine Aarhus University Hospital Aarhus Denmark
| | - K. Nagenthiraja
- Center of Functionally Integrative Neuroscience and MINDLab Aarhus University Aarhus Denmark
| | - P. Gutiérrez‐Lizardi
- Faculty of Dentistry University of Monterrey Monterrey Mexico
- Critical Care College of Nuevo León Monterrey Mexico
| | - K. Mouridsen
- Center of Functionally Integrative Neuroscience and MINDLab Aarhus University Aarhus Denmark
| | - S. N. Jespersen
- Center of Functionally Integrative Neuroscience and MINDLab Aarhus University Aarhus Denmark
- Department of Physics and Astronomy Aarhus University Aarhus Denmark
| | - E. K. Tønnesen
- Department of Anaesthesia and Intensive Care Medicine Aarhus University Hospital Aarhus Denmark
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Patry C, Orfanos SE, Rafat N. Translational research in ARDS patients: new biological phenotypes. Intensive Care Med 2015. [PMID: 26224249 DOI: 10.1007/s00134-015-4005-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Christian Patry
- Department of Pediatrics I, University Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany
| | - Stylianos E Orfanos
- Second Department of Critical Care, Attikon University Hospital, University of Athens Medical School, 1, Rimini St., 12462, Haidari, Athens, Greece
| | - Neysan Rafat
- Department of Pediatrics I, University Children's Hospital, University of Heidelberg, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
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Predictive and prognostic significance of circulating endothelial cells in advanced non-small cell lung cancer patients. Tumour Biol 2015; 36:9031-7. [DOI: 10.1007/s13277-015-3657-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 06/09/2015] [Indexed: 12/31/2022] Open
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Moussa MD, Santonocito C, Fagnoul D, Donadello K, Pradier O, Gaussem P, De Backer D, Vincent JL. Evaluation of endothelial damage in sepsis-related ARDS using circulating endothelial cells. Intensive Care Med 2015; 41:231-8. [PMID: 25510299 DOI: 10.1007/s00134-014-3589-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 11/27/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE Endothelial cell activation and dysfunction are involved in the pathophysiology of ARDS. Circulating endothelial cells (CECs) may be a useful marker of endothelial dysfunction and damage but have been poorly studied in ARDS. We hypothesized that the CEC count may be elevated in patients with sepsis-related ARDS compared to those with sepsis without ARDS. METHODS ARDS was defined according to the Berlin consensus definition. The study population included 17 patients with moderate or severe ARDS, 9 with mild ARDS, 13 with sepsis and no ARDS, 13 non-septic patients, and 12 healthy volunteers. Demographic, hemodynamic, and prognostic variables, including PaO(2)/FiO(2) ratio, 28-day survival, blood lactate, APACHE II, and SOFA score, were recorded. CECs were counted in arterial blood samples using the reference CD146 antibody-based immunomagnetic isolation and UEA1-FITC staining method. Measurements were performed 12-24 h after diagnosis of ARDS and repeated daily for 3 days. RESULTS The median day-1 CEC count was significantly higher in patients with moderate or severe ARDS than in mild ARDS or septic-control patients [27.2 (18.3-49.4) vs. 17.4 (11-24.5) cells/ml (p < 0.034), and 18.4 (9.1-31) cells/ml (p < 0.035), respectively]. All septic patients (with or without ARDS) had higher day-1 CEC counts than the non-septic patients [19.6 (14.2-30.6) vs. 10.8 (5.7-13.2) cells/ml, p = 0.002]. CONCLUSION The day-1 CEC count was significantly higher in ARDS patients than in other critically ill patients, and in moderate or severe ARDS patients compared to those with milder disease, making it a potentially useful marker of ARDS severity.
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Affiliation(s)
- Mouhamed Djahoum Moussa
- Department of Intensive Care, Erasme University Hospital, Université Libre de Bruxelles (ULB), 808 Route de Lennik, 1070, Brussels, Belgium
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