Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Translational Internal Medicine

4 Issues per year

Open Access
See all formats and pricing
More options …

Experimental models of acute respiratory distress syndrome

Emine Yilmaz Sipahi
  • Corresponding author
  • Department of Medical Pharmacology, Bulent Ecevit University, Faculty of Medicine, Zonguldak, Turkey
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-04-24 | DOI: https://doi.org/10.4103/2224-4018.147738


Acute respiratory distress syndrome (ARDS) is a major cause of morbidity, death and cost in intensive care units. ARDS was first described in 1967, and the new definition was determined as the Berlin definition in 2011 in Berlin. ARDS is a syndrome of inflammation and increased permeability of the blood-gas barrier. Despite intensive research, treatments remain limited and supportive therapies represent the mainstay of the treatment of ARDS. This inability of therapeutic modalities largely depends on the complex pathogenesis of this syndrome with multiple overlapping signaling pathways activated depending on the type of lung injury. Today, this syndrome is still associated with a high morbidity and mortality. Animal models provide us a bridge between bench and bedside. Numerous different models have been developed in order to establish the properties of ARDS, but, to date, no single animal model that mimics all of the characteristics of ARDS in humans has been developed, and most of the existing animal models are relevant only for limited aspects of human ARDS. Furthermore, each animal model has unique features that affect responses to treatment. Therefore, when choosing an animal model of ARDS, to take into account the key feature of ARDS as a working hypothesis to be tested and then create the most appropriate model to exhibit those features is important. The goal of this review is to summarize the properties of the most commonly used experimental animal models of ARDS after mentioning briefly the causes and pathophysiology.

Keywords: Acute respiratory distress syndrome; experimental models; respiratory failure


  • 1. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L. et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149:818-24.Google Scholar

  • 2. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, et al. Acute Respiratory Distress Syndrome: The Berlin Definition. JAMA 2012;307:2526-33.Google Scholar

  • 3. Fanelli V, Vlachou A, Ghannadian S, Simonett i U, Slutsky AS, Zhang H. Acute respiratory distress syndrome: New definition, current and future therapeutic options. J Thorac Dis 2013;5:326-34.Web of ScienceGoogle Scholar

  • 4. Walkey AJ, Summer R, Ho V, Alkana P. Acute respiratory distress syndrome: Epidemiology and management approaches. Clin Epidemiol 2012;4:159-69.CrossrefGoogle Scholar

  • 5. Villar J, Blanco J, Añón JM, Santos-Bouza A, Blanch L, Ambros A, et al. The ALIEN Network: İncidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensive Care Med 2011;37:1932-41.Google Scholar

  • 6. Martin TR, Matute-Bello G. Experimental models and emerging hypotheses for acute lung injury. Crit Care Clin 2011;27:735-52.Web of ScienceCrossrefGoogle Scholar

  • 7. Matt hay MA, Zimmerman GA, Esmon C, Bhatt acharya 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. Am J Respir Crit Care Med 2003;167:1027-35.Google Scholar

  • 8. Dushianthan A, Grocott MP, Postle AD, Cusack R. Acute respiratory distress syndrome and acute lung injury. Postgrad Med J 2011;87:612-22.CrossrefWeb of ScienceGoogle Scholar

  • 9. Tsushima K, King LS, Aggarwal NR, De Gorordo A, D’Alessio FR, Kubo K. Acute lung injury review. Intern Med 2009;48:621-30.Web of ScienceCrossrefGoogle Scholar

  • 10. Bellingan GJ. The pulmonary physician in critical care * 6: The pathogenesis of ALI/ARDS. Thorax 2002;57:540-6.CrossrefGoogle Scholar

  • 11. Ware LB, Matt hay MA. The acute respiratory distress syndrome. N Engl J Med 2000;342:1334-49.Google Scholar

  • 12. Boyle AJ, McNamee JJ, McAuley DF. Biological therapies in the acute respiratory distress syndrome. Expert Opin Biol Ther 2014;14:969-81.CrossrefWeb of ScienceGoogle Scholar

  • 13. Puneet P, Moochhala S, Bhatia M. Chemokines in acute respiratory dis tress syndrome. Am J Physiol Lung Cell Mol Physiol 2005;288:L3-15.Google Scholar

  • 14. Tasaka S, Hasegawa N, Ishizaka A. Pharmacology of acute lung injury. Pulm Pharmacol Ther 2002;15:83-95.CrossrefGoogle Scholar

  • 15. Varisco BM. The pharmacology of acute lung injury in sepsis. Adv Phar macol Sci 2011;2011:254619.Google Scholar

  • 16. Duggal A, Ganapathy A, Mohana Ratnapalan M, Adhikari NK. Pharmacological treatments for acute respiratory distress syndrome: Systematic review. Minerva Anestesiol 2014 Jun 17 [Epud ahead of print].Google Scholar

  • 17. Mutate-Bello G, Downey G, Moore BB, Groshong SD, Matt hay MA, Slutsky AS, et al. on behalf of the Acute Lung Injury in Animals Study Group. An official American Thoracic Society Workshop Report: Features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 2011;44:725-38.CrossrefGoogle Scholar

  • 18. Matute-Bello G, Matt hay MA. Animal models of acute lung injury. Available from: http://www.thoracic.org/clinical/critical-care/criticalcare-research/animal-models-of-acute-lung-injury.php, 2013 [Last accessed on 2014].Google Scholar

  • 19. Mutate-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2008;295:L379-99.Google Scholar

  • 20. Bastarache JA, Blackwell TS. Development of animal models for the acute respiratory distress syndrome. Dis Model Mech 2009;2:218-23.Google Scholar

  • 21. Kaynar G, Yurdakan G, Comert F, Yilmaz-Sipahi E. Effects of peripheral benzodiazepine receptor ligand Ro5-4864 in four animal models of acute lung injury. J Surg Res 2013;182:277-84.Web of ScienceCrossrefGoogle Scholar

  • 22. Tekin IO, Sipahi EY, Comert M, Acikgoz S, Yurdakan G. Low-density lipoproteins oxidized after intestinal ischemia/reperfusion in rats. J Surg Res 2009;157:e47-54.Web of ScienceGoogle Scholar

  • 23. Cunningham AL, Hurley JV. Alpha-naphthyl-thiourea-induced pulmonary oedema in the rat: A topographical and electronmicroscope study. J Pathol 1972;106:25-35.CrossrefGoogle Scholar

  • 24. Erdem MK, Yurdakan G, Yilmaz-Sipahi E. The effects of ketamine, midazolam and ketamine/xylazine on acute lung injury induced by alpha-naphthylthiourea (ANTU) in rats. Adv Clin Exp Med 2014;23:343-51.CrossrefGoogle Scholar

  • 25. Atalay F, Yurdakan G, Yilmaz-Sipahi E. The Effect of the endothelin recep tor antagonist tezosentan on acute lung injury induced by alphanaph thylthiourea in rats. Kaohsiung J Med Sci 2012;28:72-8.CrossrefGoogle Scholar

  • 26. Voelker M, Fichtner F, Kasper M, Kamprad M, Sack U, Kaisers U, et al. Characterization of a double-hit murine model of Acute Respiratory Distress Syndrome. Clin Exp Pharmacol Physiol 2014;41:844-53.CrossrefWeb of ScienceGoogle Scholar

  • 27. Varisco BM. The pharmacology of acute lung injury in sepsis. Adv Pharmacol Sci 2011;2011:254619.Google Scholar

  • 28. Everhart MB, Han W, Sherrill TP, Arutiunov M, Polosukhin VV, Burke JR, et al. Duration and intensity of NF-kappaB activity determine the severity of endotoxin-induced acute lung injury. J Immunol 2006;176:4995-5005.Google Scholar

  • 29. Dejager L, Pinheiro I, Dejonckheere E, Libert C. Cecal ligation and puncture: The gold standard model for polymicrobial sepsis? Trends Microbiol 2011;19:198-208.CrossrefWeb of ScienceGoogle Scholar

  • 30. Antonelli M, Azoulay E, Bonten M, Chastre J, Citerio G, Conti G, et al. Year in review in Intensive Care Medicine, 2008: II. Experimental, acute respiratory failure and ARDS, mechanical ventilation and endotracheal intubation. Intensive Care Med 2009;35:215-31.Web of ScienceGoogle Scholar

  • 31. Hubbard WJ, Choudhry M, Schwacha MG, Kerby JD, Rue LW 3rd, Bland KI, et al. Cecal ligation and puncture. Shock 2005;24 Suppl 1:52-7.Google Scholar

  • 32. Maier S, Traeger T, Entleutner M, Westerholt A, Kleist B, Hüser N, et al. Cecal ligation and puncture versus colon ascendens stent peritonitis: Two distinct animal models for polymicrobial sepsis. Shock 2004;21:505-11.CrossrefGoogle Scholar

  • 33. Berguer R, Alarcon A, Feng S, Gutt C. Laparoscopic cecal ligation and puncture in the rat. Surg Endosc 1997;11:1206-8.CrossrefGoogle Scholar

  • 34. Wiener-Kronish JP, Albertine KH, Matthay MA. Differential responses of the endothelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest 1991;88:864-75.CrossrefGoogle Scholar

  • 35. Lai CC, Liu WL, Chen CM. Glutamine att enuates acute lung injury caused by acid aspiration. Nutrients 2014;6:3101-16.CrossrefGoogle Scholar

  • 36. Reiss LK, Uhlig U, Uhlig S. Models and mechanisms of acute lung injury caused by direct insults. Eur J Cell Biol 2012;91:590-601.Web of ScienceCrossrefGoogle Scholar

  • 37. Fard N, Saffari A, Emami G, Hofer S, Kauczor HU, Mehrabi A. Acute respiratory distress syndrome induction by pulmonary ischemiareperfusion injury in large animal models. J Surg Res 2014;189:274-84.Google Scholar

  • 38. Lee SM, Choi H, Yang G, Park KC, Jeong S, Hong S. MicroRNAs mediate oleic acid-induced acute lung injury in rats using an alternative injury mechanism. Mol Med Rep 2014;10:292-300.Web of ScienceGoogle Scholar

  • 39. Lingappan K, Jiang W, Wang L, Couroucli XI, Barrios R, Moorthy B. Sex-specific differences in hyperoxic lung injury in mice: İmplications for acute and chronic lung disease in humans. Toxicol Appl Pharmacol 2013;272:281-90.Google Scholar

  • 40. Muellenbach RM, Kredel M, Zollhoefer B, 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. Exp Lung Res 2009;35:222-33.CrossrefWeb of ScienceGoogle Scholar

  • 41. Sipahi E, Hodoglugil U, Ercan ZS, Turker RK. Acute effect of endothelin-1 on lung oedema induced by alphanaphthylthiourea (ANTU). Pharmacol Res 1996;33:375-8.CrossrefGoogle Scholar

  • 42. Sipahi E, Hodoglugil U, Ustun H, Zengil H, Turker RK, Ercan ZS. An unexpected interaction between NG-nitro-Larginine methyl ester and L-arginine in alphanaphthylthiourea-induced pulmonary oedema in rats. Eur J Pharmacol 1997;321:45-51.Google Scholar

  • 43. Sipahi EY, Ozel Tekin I, Comert M, Barut F, Ustun H, Sipahi TH. Oxidized low-density lipoproteins accumulate in rat lung after experimental lung edema induced by alphanaphthylthiourea (ANTU). Pharmacol Res 2004;50:585-91.CrossrefGoogle Scholar

  • 44. Comert M, Sipahi EY, Ustun H, Isikdemir F, Numanoglu G, Barut F, et al. Morphine modulates inducible nitric oxide synthase expression and reduces pulmonary oedema induced by alpha-naphthylthiourea. Eur J Pharmacol 2005;511:183-9.Google Scholar

  • 45. Sipahi E, Ustun H, Niyazi Ayoglu F. Acute effects of thiopental, pentobarbital and urethane on lung oedema induced by alpha naphtylthiourea (ANTU). Pharmacol Res 2002;45:235-9.CrossrefGoogle Scholar

  • 46. Hanci V, Yurdakan G, Yurtlu S, Turan IO, Sipahi EY. Protective effect of dexmedetomidine in a rat model of a-naphthylthiourea-induced acute lung injury. J Surg Res 2012;178:424-30.Google Scholar

  • 47. Richter CP. The physiology and cytology of pulmonary edema and pleural effusion produced in rats by alpha-naphthyl thiourea (ANTU). J Thorac Surg 1952;23:66-91. Google Scholar

About the article

Published Online: 2015-04-24

Published in Print: 2014-12-01

Citation Information: Journal of Translational Internal Medicine, Volume 2, Issue 4, Pages 154–159, ISSN (Online) 2224-4018, DOI: https://doi.org/10.4103/2224-4018.147738.

Export Citation

© 2015. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Comments (0)

Please log in or register to comment.
Log in