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From preclinical to clinical models of acute respiratory distress syndrome

  • Ruoyang Zhai1
  • Woodys Lenga Ma Bonda1
  • Gustavo Matute-Bello2,3
  • Matthieu Jabaudon1,4

1GReD, Université Clermont Auvergne, CNRS, INSERM, 63000 Clermont-Ferrand, France

2Center for Lung Biology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA 98105, USA

3Medical Research Service, VA Puget Sound Healthcare System, Seattle, WA 98105, USA

4Department of Perioperative Medicine, CHU Clermont-Ferrand, 63000 Clermont-Ferrand, France

DOI: 10.22514/sv.2021.228

Submitted: 12 August 2021 Accepted: 24 September 2021

Online publish date: 10 November 2021

*Corresponding Author(s): Matthieu Jabaudon E-mail:


Various preclinical models that mimic the clinical causes of acute respiratory distress syndrome (ARDS) have been used to better understand the mechanisms of acute lung injury and its repair and to investigate novel therapies targeting such mechanisms. Despite important preclinical and clinical research efforts in recent decades, few candidate therapies with promising preclinical effects have been successfully translated into the clinical scenario, which could be attributable to the intrinsic limitations of the models as well as to the incorrect identification of appropriate phenotypes of patients to target with novel therapies that have proven beneficial in select preclinical models. However, current translational research strategies based on the use of multiple complementary preclinical and clinical models hold the promise of revolutionizing intensive care by using granular knowledge that should allow for a better diagnosis, greater predictability of the disease course, and the development of targeted therapies while ensuring patient safety through reduced adverse effects. Our goal was to summarize the strengths and limitations of the available models of ARDS, including animal, in vitro, and clinical models, and to discuss the current challenges and perspectives for research.


Acute respiratory distress syndrome; Acute lung injury; Preclinical models; Transla-tional research

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Ruoyang Zhai,Woodys Lenga Ma Bonda,Gustavo Matute-Bello,Matthieu Jabaudon. From preclinical to clinical models of acute respiratory distress syndrome. Signa Vitae. 2021.doi:10.22514/sv.2021.228.


[1] ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. Journal of the American Medical Association. 2012; 307: 2526–33.

[2] Thompson BT, Chambers RC, Liu KD. Acute Respiratory Distress Syndrome. The New England Journal of Medicine. 2017; 377: 562–572.

[3] Matthay MA, Zemans RL, Zimmerman GA, Arabi YM, Beitler JR, Mercat A, et al. Acute respiratory distress syndrome. Nature Reviews Disease Primers. 2019; 5: 18.

[4] Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. Acute respiratory distress in adults. Lancet. 1967; 2: 319–323.

[5] Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. Journal of the American Medical Association. 2016; 315: 788–800.

[6] Matthay MA, Zimmerman GA, Esmon C, Bhattacharya J, Coller B, Doerschuk CM, et al. Future research directions in acute lung injury: summary of a National Heart, Lung, and Blood Institute working group. American Journal of Respiratory and Critical Care Medicine. 2003; 167: 1027–1035.

[7] Matthay MA, McAuley DF, Ware LB. Clinical trials in acute respiratory distress syndrome: challenges and opportunities. The Lancet Respiratory Medicine. 2018; 5: 524–534.

[8] Calfee CS, Eisner MD, Ware LB, Thompson BT, Parsons PE, Wheeler AP, et al. Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders. Critical Care Medicine. 2007; 35: 2243–2250.

[9] Tejera P, Meyer NJ, Chen F, Feng R, Zhao Y, O’Mahony DS, et al. Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin. Journal of Medical Genetics. 2012; 49: 671–680.

[10] Delucchi K, Famous KR, Ware LB, Parsons PE, Thompson BT, Calfee CS. Stability of ARDS subphenotypes over time in two randomised controlled trials. Thorax. 2018; 73: 439–445.

[11] Wilson JG, Calfee CS. ARDS Subphenotypes: Understanding a Heterogeneous Syndrome. Critical Care. 2020; 24: 102.

[12] Juffermans NP, Radermacher P, Laffey JG. The importance of discovery science in the development of therapies for the critically ill. Intensive Care Medicine Experimental. 2020; 8: 17.

[13] Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2008; 295: L379–L399.

[14] Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS, et al. An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. American Journal of Respiratory Cell and Molecular Biology. 2011; 44: 725–738.

[15] Matthay MA. Resolution of pulmonary edema. Thirty years of progress. American Journal of Respiratory and Critical Care Medicine. 2014; 189: 1301–1308.

[16] Oakley C, Koh M, Baldi R, Soni S, O’Dea K, Takata M, et al. Ventilation following established ARDS: a preclinical model framework to improve predictive power. Thorax. 2019; 74: 1120–1129.

[17] Laffey JG, Kavanagh BP. Fifty Years of Research in ARDS. Insight into Acute Respiratory Distress Syndrome. From Models to Patients. American Journal of Respiratory and Critical Care Medicine. 2017; 196: 18–28.

[18] Bastarache JA, Blackwell TS. Development of animal models for the acute respiratory distress syndrome. Disease Models & Mechanisms. 2009; 2: 218–223.

[19] Aeffner F, Bolon B, Davis IC. Mouse Models of Acute Respiratory Distress Syndrome: a Review of Analytical Approaches, Pathologic Features, and Common Measurements. Toxicologic Pathology. 2015; 43: 1074–1092.

[20] Cockrell AS, Yount BL, Scobey T, Jensen K, Douglas M, Beall A, et al. A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nature Microbiology. 2016; 2: 16226.

[21] Lu Y, Yeh W, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008; 42: 145–151.

[22] Ciesielska A, Matyjek M, Kwiatkowska K. TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling. Cellular and Molecular Life Sciences. 2021; 78: 1233–1261.

[23] Cheng D, Han W, Chen SM, Sherrill TP, Chont M, Park G, et al. Airway epithelium controls lung inflammation and injury through the NF-kappa B pathway. Journal of Immunology. 2007; 178: 6504–6513.

[24] Kohman RA, Crowell B, Kusnecov AW. Differential sensitivity to endotoxin exposure in young and middle-age mice. Brain, Behavior, and Immunity. 2010; 24: 486–492.

[25] Tapping RI, Akashi S, Miyake K, Godowski PJ, Tobias PS. Toll-like receptor 4, but not toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides. Journal of Immunology. 2000; 165: 5780–5787.

[26] Su X, Looney MR, Gupta N, Matthay MA. Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2009; 297: L1–L5.

[27] Matthay MA, Goolaerts A, Howard JP, Lee JW. Mesenchymal stem cells for acute lung injury: preclinical evidence. Critical Care Medicine. 2010; 38: S569–S573.

[28] Asmussen S, Ito H, Traber DL, Lee JW, Cox RA, Hawkins HK, et al. Human mesenchymal stem cells reduce the severity of acute lung injury in a sheep model of bacterial pneumonia. Thorax. 2014; 69: 819–825.

[29] Rosas LE, Doolittle LM, Joseph LM, El-Musa H, Novotny MV, Hickman-Davis JM, et al. Postexposure Liponucleotide Prophylaxis and Treatment Attenuates Acute Respiratory Distress Syndrome in Influenza-infected Mice. American Journal of Respiratory Cell and Molecular Biology. 2021; 64: 677–686.

[30] Cleary SJ, Pitchford SC, Amison RT, Carrington R, Robaina Cabrera CL, Magnen M, et al. Animal models of mechanisms of SARS-CoV-2 infection and COVID-19 pathology. British Journal of Pharmacology. 2020; 177: 4851–65.

[31] Marik PE. Aspiration pneumonitis and aspiration pneumonia. The New England Journal of Medicine. 2001; 344: 665–671.

[32] Raghavendran K, Nemzek J, Napolitano LM, Knight PR. Aspiration-induced lung injury. Critical Care Medicine. 2011; 39: 818–826.

[33] Patel BV, Wilson MR, Takata M. Resolution of acute lung injury and inflammation: a translational mouse model. The European Respiratory Journal. 2012; 39: 1162–1170.

[34] Jabaudon M, Blondonnet R, Roszyk L, Bouvier D, Audard J, Clairefond G, et al. Soluble Receptor for Advanced Glycation End-Products Predicts Impaired Alveolar Fluid Clearance in Acute Respiratory Distress Syndrome. American Journal of Respiratory and Critical Care Medicine. 2015; 192: 191–199.

[35] Chimenti L, Morales-Quinteros L, Puig F, Camprubi-Rimblas M, Guillamat-Prats R, Gómez MN, et al. Comparison of direct and indirect models of early induced acute lung injury. Intensive Care Medicine Experimental. 2020; 8: 62.

[36] Traeger T, Koerner P, Kessler W, Cziupka K, Diedrich S, Busemann A, et al. Colon ascendens stent peritonitis (CASP)–a standardized model for polymicrobial abdominal sepsis. Journal of Visualized Experiments. 2010; 46: 2299.

[37] Kuhn R, Schubert D, Tautenhahn J, Nestler G, Schulz H, Bartelmann M, et al. Effect of intraperitoneal application of an endotoxin inhibitor on survival time in a laparoscopic model of peritonitis in rats. World Journal of Surgery. 2005; 29: 766–770.

[38] Matute-Bello G, Frevert CW, Kajikawa O, Skerrett SJ, Goodman RB, Park DR, et al. Septic shock and acute lung injury in rabbits with peritonitis: failure of the neutrophil response to localized infection. American Journal of Respiratory and Critical Care Medicine. 2001; 163: 234–243.

[39] Shaver CM, Paul MG, Putz ND, Landstreet SR, Kuck JL, Scarfe L, et al. Cell-free hemoglobin augments acute kidney injury during experimental sepsis. American Journal of Physiology-Renal Physiology. 2019; 317: F922–F929.

[40] Meegan JE, Shaver CM, Putz ND, Jesse JJ, Landstreet SR, Lee HNR, et al. Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis. PLoS ONE. 2020; 15: e0228727.

[41] Wynn JL, Scumpia PO, Delano MJ, O’Malley KA, Ungaro R, Abouhamze A, et al. Increased mortality and altered immunity in neonatal sepsis produced by generalized peritonitis. Shock. 2007; 28: 675–683.

[42] Webb HH, Tierney DF. Experimental pulmonary edema due to intermit-tent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure. American Review of Respiratory Disease. 1974; 110: 556–565.

[43] Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. American Journal of Respiratory and Critical Care Medicine. 1998; 157: 294–323.

[44] Kallet RH, Matthay MA. Hyperoxic Acute Lung Injury. Respiratory Care. 2013; 58: 123–141.

[45] Vuichard D, Ganter MT, Schimmer RC, Suter D, Booy C, Reyes L, et al. Hypoxia aggravates lipopolysaccharide-induced lung injury. Clinical and Experimental Immunology. 2005; 141: 248–260.

[46] Hauser B, Barth E, Bassi G, Simon F, Gröger M, Öter S, et al. Hemodynamic, metabolic, and organ function effects of pure oxygen ventilation during established fecal peritonitis-induced septic shock. Critical Care Medicine. 2009; 37: 2465–2469.

[47] Eltzschig HK, Eckle T. Ischemia and reperfusion–from mechanism to translation. Nature Medicine. 2011; 17: 1391–1401.

[48] Regelin N, Heyder S, Laschke MW, Hadizamani Y, Borgmann M, Moehrlen U, et al. A murine model to study vasoreactivity and intravascular flow in lung isograft microvessels. Scientific Reports. 2019; 9: 5170.

[49] Fard N, Saffari A, Emami G, Hofer S, Kauczor H, Mehrabi A. Acute respiratory distress syndrome induction by pulmonary ischemia–reperfusion injury in large animal models. Journal of Surgical Research. 2014; 189: 274–284.

[50] Rocco PRM, Nieman GF. ARDS: what experimental models have taught us. Intensive Care Medicine. 2016; 42: 806–810.

[51] Su HC, Nguyen KB, Salazar-Mather TP, Ruzek MC, Dalod MY, Biron CA. NK cell functions restrain T cell responses during viral infections. European Journal of Immunology. 2001; 31: 3048–3055.

[52] Lang PA, Lang KS, Xu HC, Grusdat M, Parish IA, Recher M, et al. Natural killer cell activation enhances immune pathology and promotes chronic infection by limiting CD8+ T-cell immunity. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109: 1210–1215.

[53] Zhou G, Juang SWW, Kane KP. NK cells exacerbate the pathology of influenza virus infection in mice. European Journal of Immunology. 2013; 43: 929–938.

[54] Johansen MD, Irving A, Montagutelli X, Tate MD, Rudloff I, Nold MF, et al. Animal and translational models of SARS-CoV-2 infection and COVID-19. Mucosal Immunology. 2020; 13: 877–891.

[55] Hendrickson CM, Matthay MA. Viral pathogens and acute lung injury: investigations inspired by the SARS epidemic and the 2009 H1N1 influenza pandemic. Seminars in Respiratory and Critical Care Medicine. 2013; 34: 475–486.

[56] Schuster DP. ARDS: clinical lessons from the oleic acid model of acute lung injury. American Journal of Respiratory and Critical Care Medicine. 1994; 149: 245–260.

[57] Hartmann EK, Bentley A, Duenges B, Klein KU, Boehme S, Markstaller K, et al. TIP peptide inhalation in oleic acid-induced experimental lung injury: a post-hoc comparison. BMC Research Notes. 2013; 6: 385.

[58] Prat NJ, Meyer AD, Langer T, Montgomery RK, Parida BK, Batchinsky AI, et al. Low-Dose Heparin Anticoagulation during Extracorporeal Life Support for Acute Respiratory Distress Syndrome in Conscious Sheep. Shock. 2015; 44: 560–568.

[59] Du G, Wang S, Li Z, Liu J. Sevoflurane Posttreatment Attenuates Lung Injury Induced by Oleic Acid in Dogs. Anesthesia and Analgesia. 2017; 124: 1555–1563.

[60] Ballard-Croft C, Wang D, Sumpter LR, Zhou X, Zwischenberger JB. Large-Animal Models of Acute Respiratory Distress Syndrome. The Annals of Thoracic Surgery. 2012; 93: 1331–1339.

[61] Raghavendran K, Willson D, Notter RH. Surfactant therapy for acute lung injury and acute respiratory distress syndrome. Critical Care Clinics. 2011; 27: 525–559.

[62] Muellenbach RM, Kredel M, Bernd Z, Johannes A, Kuestermann J, Schuster F, et al. Acute respiratory distress induced by repeated saline lavage provides stable experimental conditions for 24 hours in pigs. Experimental Lung Research. 2009; 35: 222–233.

[63] Russ M, Boerger E, von Platen P, Francis RCE, Taher M, Boemke W, et al. Surfactant Depletion Combined with Injurious Ventilation Results in a Reproducible Model of the Acute Respiratory Distress Syndrome (ARDS). Journal of Visualized Experiments. 2021.

[64] Zhai R, Blondonnet R, Ebrahimi E, Belville C, Audard J, Gross C, et al. The receptor for advanced glycation end-products enhances lung epithelial wound repair: an in vitro study. Experimental Cell Research. 2020; 391: 112030.

[65] Lee JW, Fang X, Dolganov G, Fremont RD, Bastarache JA, Ware LB, et al. Acute lung injury edema fluid decreases net fluid transport across human alveolar epithelial type II cells. The Journal of Biological Chemistry. 2007; 282: 24109–24119.

[66] Fang X, Matthay MA. Measurement of Protein Permeability and Fluid Transport of Human Alveolar Epithelial Type II Cells under Pathological Conditions. Methods in Molecular Biology. 2018; 122: 121–128.

[67] Drasler B, Karakocak BB, Tankus EB, Barosova H, Abe J, Sousa de Almeida M, et al. An Inflamed Human Alveolar Model for Testing the Efficiency of Anti-inflammatory Drugs in vitro. Frontiers in Bioengineering and Biotechnology. 2020; 8: 987.

[68] King P. Haemophilus influenzae and the lung (Haemophilus and the lung). Clinical and Translational Medicine. 2012; 1: 10.

[69] Camprubí–Rimblas M, Guillamat-Prats R, Lebouvier T, Bringué J, Chimenti L, Iglesias M, et al. Role of heparin in pulmonary cell populations in an in-vitro model of acute lung injury. Respiratory Research. 2017; 18: 89.

[70] Tojo K, Tamada N, Nagamine Y, Yazawa T, Ota S, Goto T. Enhancement of glycolysis by inhibition of oxygen‐sensing prolyl hydroxylases protects alveolar epithelial cells from acute lung injury. The FASEB Journal. 2018; 32: 2258–2268.

[71] Pooladanda V, Thatikonda S, Bale S, Pattnaik B, Sigalapalli DK, Bathini NB, et al. Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation. Cell Death & Disease. 2019; 10: 81.

[72] Wu D, Fu X, Zhang Y, Li Q, Ye L, Han S, et al. The protective effects of C16 peptide and angiopoietin-1 compound in lipopolysaccharide-induced acute respiratory distress syndrome. Experimental Biology and Medicine. 2020; 245: 1683–1696.

[73] Bastarache JA, Wang L, Geiser T, Wang Z, Albertine KH, Matthay MA, et al. The alveolar epithelium can initiate the extrinsic coagulation cascade through expression of tissue factor. Thorax. 2007; 62: 608–616.

[74] Metz JK, Wiegand B, Schnur S, Knoth K, Schneider-Daum N, Groß H, et al. Modulating the Barrier Function of Human Alveolar Epithelial (hAELVi) Cell Monolayers as a Model of Inflammation. Alternatives to Laboratory Animals. 2020; 48: 252–267.

[75] Otulakowski G, Engelberts D, Gusarova GA, Bhattacharya J, Post M, Kavanagh BP. Hypercapnia attenuates ventilator-induced lung injury via a disintegrin and metalloprotease-17. The Journal of Physiology. 2016; 592: 4507–4521.

[76] Wang T, Gross C, Desai A, Zemskov E, Wu X, Garcia AN, et al. Endothelial Cell Signaling and Ventilator-Induced Lung Injury (VILI): Molecular Mechanisms, Genomic Analyses & Therapeutic Targets. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2017; 312: L452–L476.

[77] Joelsson JP, Myszor IT, Arason AJ, Ingthorsson S, Cherek P, Windels GS, et al. Innovative in vitro method to study ventilator induced lung injury. ALTEX. 2019; 36: 634–642.

[78] Monjezi M, Jamaati H, Noorbakhsh F. Attenuation of ventilator-induced lung injury through suppressing the pro-inflammatory signaling pathways: a review on preclinical studies. Molecular Immunology. 2021; 135: 127–136.

[79] Pao H-P, Liao W-I, Tang S-E, Wu S-Y, Huang K-L, Chu S-J. Suppression of Endoplasmic Reticulum Stress by 4-PBA Protects Against Hyperoxia-Induced Acute Lung Injury via Up-Regulating Claudin-4 Expression. Frontiers in Immunology. 2021; 12: 674316.

[80] Fitzgerald KA, Malhotra M, Curtin CM, O’ Brien FJ, O’ Driscoll CM. Life in 3D is never flat: 3D models to optimise drug delivery. Journal of Controlled Release. 2015; 215: 39–54.

[81] Rothen-Rutishauser BM, Kiama SG, Gehr P. A three-dimensional cellular model of the human respiratory tract to study the interaction with particles. American Journal of Respiratory Cell and Molecular Biology. 2005; 32: 281–289.

[82] Blank F, Rothen-Rutishauser B, Gehr P. Dendritic cells and macrophages form a transepithelial network against foreign particulate antigens. American Journal of Respiratory Cell and Molecular Biology. 2007; 36: 669–677.

[83] Viola H, Chang J, Grunwell JR, Hecker L, Tirouvanziam R, Grotberg JB, et al. Microphysiological systems modeling acute respiratory distress syndrome that capture mechanical force-induced injury-inflammation-repair. APL Bioengineering. 2019; 3: 041503.

[84] Nikolić MZ, Rawlins EL. Lung Organoids and their Use to Study Cell-Cell Interaction. Current Pathobiology Reports. 2017; 5: 223–231.

[85] Katsura H, Sontake V, Tata A, Kobayashi Y, Edwards CE, Heaton BE, et al. Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction. Cell Stem Cell. 2020; 27: 890–904.e8.

[86] Salahudeen AA, Choi SS, Rustagi A, Zhu J, van Unen V, de la O SM, et al. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. Nature. 2020; 588: 670–675.

[87] Youk J, Kim T, Evans KV, Jeong Y, Hur Y, Hong SP, et al. Three-Dimensional Human Alveolar Stem Cell Culture Models Reveal Infection Response to SARS-CoV-2. Cell Stem Cell. 2020; 27: 905–919.e10.

[88] Huh D, Leslie DC, Matthews BD, Fraser JP, Jurek S, Hamilton GA, et al. A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice. Science Translational Medicine. 2012; 4: 159ra147.

[89] Meyer NJ, Calfee CS. Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome. the Lancet. Respiratory Medicine. 2017; 5: 512–523.

[90] da Silva da Costa FA, Soares MR, Malagutti-Ferreira MJ, da Silva GR, Lívero FADR, Ribeiro-Paes JT. Three-Dimensional Cell Cultures as a Research Platform in Lung Diseases and COVID-19. Tissue Engineering and Regenerative Medicine. 2021; 18: 735–745.

[91] Huang D, Liu T, Liao J, Maharjan S, Xie X, Pérez M, et al. Reversed-engineered human alveolar lung-on-a-chip model. Proceedings of the National Academy of Sciences. 2021; 118: e2016146118.

[92] Wyshock EG, Suffredini AF, Parrillo JE, Colman RW. Cofactors V and VIII after endotoxin administration to human volunteers. Thrombosis Research. 1995; 80: 377–389.

[93] DeLa Cadena RA, Majluf-Cruz A, Stadnicki A, Agosti JM, Colman RW, Suffredini AF. Activation of the contact and fibrinolytic systems after intravenous administration of endotoxin to normal human volunteers: correlation with the cytokine profile. Immunopharmacology. 1996; 33: 231–237.

[94] Luca R, Lijnen HR, Suffredini AF, Pepper MS, Steinberg KP, Martin TR, et al. Increased angiostatin levels in bronchoalveolar lavage fluids from ARDS patients and from human volunteers after lung instillation of endotoxin. Thrombosis and Haemostasis. 2002; 87: 966–971.

[95] Martin TR, Pistorese BP, Chi EY, Goodman RB, Matthay MA. Effects of leukotriene B4 in the human lung. Recruitment of neutrophils into the alveolar spaces without a change in protein permeability. The Journal of Clinical Investigation. 1989; 84: 1609–1619.

[96] Shyamsundar M, McKeown STW, O’Kane CM, Craig TR, Brown V, Thickett DR, et al. Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers. American Journal of Respiratory and Critical Care Medicine. 2009; 179: 1107–1114.

[97] Shyamsundar M, McAuley DF, Ingram RJ, Gibson DS, O’Kane D, McKeown ST, et al. Keratinocyte growth factor promotes epithelial survival and resolution in a human model of lung injury. American Journal of Respiratory and Critical Care Medicine. 2014; 189: 1520–1529.

[98] Moazed F, Burnham EL, Vandivier RW, O’Kane CM, Shyamsundar M, Hamid U, et al. Cigarette smokers have exaggerated alveolar barrier disruption in response to lipopolysaccharide inhalation. Thorax. 2016; 71: 1130–1136.

[99] Hamid U, Krasnodembskaya A, Fitzgerald M, Shyamsundar M, Kissenpfennig A, Scott C, et al. Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS. Thorax. 2017; 72: 971–980.

[100] Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proceedings of the National Academy of Sciences. 2009; 106: 16357–16362.

[101] Ross JT, Nesseler N, Lee J, Ware LB, Matthay MA. The ex vivo human lung: research value for translational science. JCI Insight. 2019; 4: e128833.

[102] Shaver CM, Ware LB. Primary graft dysfunction: pathophysiology to guide new preventive therapies. Expert Review of Respiratory Medicine. 2017; 11: 119–128.

[103] Beitler JR, Goligher EC, Schmidt M, Spieth PM, Zanella A, Martin-Loeches I, et al. Personalized medicine for ARDS: the 2035 research agenda. Intensive Care Medicine. 2016; 42: 756–767.

[104] Jagrosse ML, Dean DA, Rahman A, Nilsson BL. RNAi therapeutic strategies for acute respiratory distress syndrome. Translational Research. 2019; 214: 30–49.

[105] Jabaudon M, Blondonnet R, Audard J, Fournet M, Godet T, Sapin V, et al. Recent directions in personalised acute respiratory distress syndrome medicine. Anaesthesia Critical Care & Pain Medicine. 2018; 37: 251–258.

[106] Matthay MA, Arabi YM, Siegel ER, Ware LB, Bos LDJ, Sinha P, et al. Phenotypes and personalized medicine in the acute respiratory distress syndrome. Intensive Care Medicine. 2020; 46: 2136–2152.

[107] Jabaudon M, Blondonnet R, Ware LB. Biomarkers in acute respiratory distress syndrome. Current Opinion in Critical Care. 2021; 27: 46–54.

[108] Jabaudon M, Futier E, Roszyk L, Chalus E, Guerin R, Petit A, et al. Soluble form of the receptor for advanced glycation end products is a marker of acute lung injury but not of severe sepsis in critically ill patients. Critical Care Medicine. 2011; 39: 480–488.

[109] Mrozek S, Jabaudon M, Jaber S, Paugam-Burtz C, Lefrant J, Rouby J, et al. Elevated Plasma Levels of sRAGE are Associated with Nonfocal CT-Based Lung Imaging in Patients with ARDS: a Prospective Multicenter Study. Chest. 2016; 150: 998–1007.

[110] Sinha P, Calfee CS. Phenotypes in acute respiratory distress syndrome: moving towards precision medicine. Current Opinion in Critical Care. 2019; 25: 12–20.

[111] Jabaudon M, Audard J, Pereira B, Jaber S, Lefrant J-Y, Blondonnet R, et al. Early Changes Over Time in the Radiographic Assessment of Lung Edema Score Are Associated With Survival in ARDS. Chest. 2020; 158: 2394–2403.

[112] Jabaudon M, Pereira B, Laroche E, Roszyk L, Blondonnet R, Audard J, et al. Changes in Plasma Soluble Receptor for Advanced Glycation End-Products Are Associated with Survival in Patients with Acute Respiratory Distress Syndrome. Journal of Clinical Medicine Research. 2021; 10: 2076.

[113] Sinha P, Calfee CS, Cherian S, Brealey D, Cutler S, King C, et al. Prevalence of phenotypes of acute respiratory distress syndrome in critically ill patients with COVID-19: a prospective observational study. The Lancet Respiratory Medicine. 2020; 8: 1209–1218.

[114] Carla A, Pereira B, Boukail H, Audard J, Pinol-Domenech N, De Carvalho M, et al. Acute respiratory distress syndrome subphenotypes and therapy responsive traits among preclinical models: protocol for a systematic review and meta-analysis. Respiratory Research. 2020; 21: 81.

[115] Papazian L, Forel J, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. The New England Journal of Medicine. 2010; 363: 1107–1116.

[116] Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, et al. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. The New England Journal of Medicine. 2000; 342: 1301–1308.

[117] Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respiratory Medicine. 2020; 8: 267–276.

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IndexCopernicus The Index Copernicus International (ICI) Journals database’s is an international indexation database of scientific journals. It covered international scientific journals which divided into general information, contents of individual issues, detailed bibliography (references) sections for every publication, as well as full texts of publications in the form of attached files (optional). For now, there are more than 58,000 scientific journals registered at ICI.

Geneva Foundation for Medical Education and Research The Geneva Foundation for Medical Education and Research (GFMER) is a non-profit organization established in 2002 and it works in close collaboration with the World Health Organization (WHO). The overall objectives of the Foundation are to promote and develop health education and research programs.

Scopus: CiteScore 0.5(2019) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.

Embase Embase (often styled EMBASE for Excerpta Medica dataBASE), produced by Elsevier, is a biomedical and pharmacological database of published literature designed to support information managers and pharmacovigilance in complying with the regulatory requirements of a licensed drug.

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