Mouse Models of Acute Lung Injury

  • William A. AltemeierEmail author
  • Chi F. Hung
  • Gustavo Matute-Bello
Part of the Respiratory Medicine book series (RM)


Acute respiratory distress syndrome or ARDS remains a devastating complication of critical illness, resulting in significant annual morbidity, mortality, and healthcare expenditures. Although much is known about the physiology of ARDS, many aspects of its pathogenesis remain incompletely understood, and no effective pharmacologic therapies have been identified to date. Because of this, research focused on ARDS and its preclinical animal model correlate, acute lung injury, remains a priority for scientists focused on lung diseases, critical illness, and trauma. Mouse model systems allow the use of genetic models and a wide range of reagents to pursue highly mechanistic studies into the cellular and molecular mechanisms of acute lung injury. However, the challenges of using mice to study acute lung injury include identifying appropriate, clinically relevant models and integrating cellular and molecular data with physiological measurements of lung injury. This chapter provides a brief review of the advantages and challenges of mouse models and reviews different models of acute lung injury. It also includes practical information on specific methods to help the new investigator develop mouse models of acute lung injury in his or her laboratory.


Acute lung injury Mouse model Pneumonia Ventilator-induced lung injury Hyperoxia 


  1. 1.
    Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, et al. Incidence and outcomes of acute lung injury. N Engl J Med. 2005;353:1685–93. doi: 10.1056/NEJMoa050333.CrossRefPubMedGoogle Scholar
  2. 2.
    Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med. 1995;151:293–301.CrossRefPubMedGoogle Scholar
  3. 3.
    Jia X, Malhotra A, Saeed M, Mark RG, Talmor D. Risk factors for ARDS in patients receiving mechanical ventilation for > 48 h. Chest. 2008;133:853–61. doi: 10.1378/chest.07-1121.CrossRefPubMedGoogle Scholar
  4. 4.
    Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, et al. Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med. 2004;32:1817–24. doi: 10.1097/01.CCM.0000133019.52531.30.CrossRefPubMedGoogle Scholar
  5. 5.
    Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49. doi: 10.1056/NEJM200005043421806.CrossRefPubMedGoogle Scholar
  6. 6.
    ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. 2012. p. 2526–33. doi: 10.1001/jama.2012.5669.
  7. 7.
    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. 2011. p. 725–38. doi: 10.1165/rcmb.2009-0210ST.
  8. 8.
    Lorè NI, Iraqi FA, Bragonzi A. Host genetic diversity influences the severity of Pseudomonas aeruginosa pneumonia in the Collaborative Cross mice. BMC Genet. 2015;16:106. doi: 10.1186/s12863-015-0260-6.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ferris MT, Aylor DL, Bottomly D, Whitmore AC, Aicher LD, Bell TA, et al. Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog. 2013;9:e1003196. doi: 10.1371/journal.ppat.1003196.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Prows DR, Gibbons WJ, Smith JJ, Pilipenko V, Martin LJ. Age and sex of mice markedly affect survival times associated with hyperoxic acute lung injury. PLoS ONE. 2015;10:e0130936. doi: 10.1371/journal.pone.0130936.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rutledge H, Aylor DL, Carpenter DE, Peck BC, Chines P, Ostrowski LE, et al. Genetic regulation of Zfp30, CXCL1, and neutrophilic inflammation in murine lung. Genetics. 2014;198:735–45. doi: 10.1534/genetics.114.168138.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Nichols JL, Gladwell W, Verhein KC, Cho H-Y, Wess J, Suzuki O, et al. Genome-wide association mapping of acute lung injury in neonatal inbred mice. FASEB J. 2014;28:2538–50. doi: 10.1096/fj.13-247221.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Howden R, Cho H-Y, Miller-DeGraff L, Walker C, Clark JA, Myers PH, et al. Cardiac physiologic and genetic predictors of hyperoxia-induced acute lung injury in mice. Am J Respir Cell Mol Biol. 2012;46:470–8. doi: 10.1165/rcmb.2011-0204OC.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Alm A-S, Li K, Chen H, Wang D, Andersson R, Wang X. Variation of lipopolysaccharide-induced acute lung injury in eight strains of mice. Respir Physiol Neurobiol. 2010;171:157–64. doi: 10.1016/j.resp.2010.02.009.CrossRefPubMedGoogle Scholar
  15. 15.
    Hudak BB, Zhang LY, Kleeberger SR. Inter-strain variation in susceptibility to hyperoxic injury of murine airways. Pharmacogenetics. 1993;3:135–43.CrossRefPubMedGoogle Scholar
  16. 16.
    Chia R, Achilli F, Festing MFW, Fisher EMC. The origins and uses of mouse outbred stocks. Nat Genet. 2005;37:1181–6. doi: 10.1038/ng1665.CrossRefPubMedGoogle Scholar
  17. 17.
    Festing MFW. Principles: the need for better experimental design. Trends Pharmacol Sci. 2003;24:341–5. doi: 10.1016/S0165-6147(03)00159-7.CrossRefPubMedGoogle Scholar
  18. 18.
    Prows DR, Winterberg AV, Gibbons WJ, Burzynski BB, Liu C, Nick TG. Reciprocal backcross mice confirm major loci linked to hyperoxic acute lung injury survival time. Physiol Genomics. 2009;38:158–68. doi: 10.1152/physiolgenomics.90392.2008.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Šarić A, Sobočanec S, Šafranko ŽM, Popović-Hadžija M, Aralica G, Korolija M, et al. Female headstart in resistance to hyperoxia-induced oxidative stress in mice. Acta Biochim Pol. 2014;61:801–7.PubMedGoogle Scholar
  20. 20.
    Lingappan K, Jiang W, Wang L, Couroucli XI, Moorthy B. Sex-specific differences in hyperoxic lung injury in mice: role of cytochrome P450 (CYP)1A. Toxicology. 2015;331:14–23. doi: 10.1016/j.tox.2015.01.019.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Redente EF, Jacobsen KM, Solomon JJ, Lara AR, Faubel S, Keith RC, et al. Age and sex dimorphisms contribute to the severity of bleomycin-induced lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2011;301:L510–8. doi: 10.1152/ajplung.00122.2011.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Babin AL, Cannet C, Gérard C, Saint-Mezard P, Page CP, Sparrer H, et al. Bleomycin-induced lung injury in mice investigated by MRI: model assessment for target analysis. Magn Reson Med. 2012;67:499–509. doi: 10.1002/mrm.23009.CrossRefPubMedGoogle Scholar
  23. 23.
    Gharaee-Kermani M, Hatano K, Nozaki Y, Phan SH. Gender-based differences in bleomycin-induced pulmonary fibrosis. Am J Pathol. 2005;166:1593–606. doi: 10.1016/S0002-9440(10)62470-4.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509:282–3.CrossRefPubMedGoogle Scholar
  25. 25.
    Iskander KN, Craciun FL, Stepien DM, Duffy ER, Kim J, Moitra R, et al. Cecal ligation and puncture-induced murine sepsis does not cause lung injury. Crit Care Med. 2013;41:154–65. doi: 10.1097/CCM.0b013e3182676322.CrossRefPubMedCentralGoogle Scholar
  26. 26.
    Altemeier WA, Matute-Bello G, Gharib SA, Glenny RW, Martin TR, Liles WC. Modulation of lipopolysaccharide-induced gene transcription and promotion of lung injury by mechanical ventilation. J Immunol. 2005;175:3369–76.CrossRefPubMedGoogle Scholar
  27. 27.
    Hu G, Malik AB, Minshall RD. Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. Crit Care Med. 2010;38:194–201. doi: 10.1097/CCM.0b013e3181bc7c17.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Chun CD, Liles WC, Frevert CW, Glenny RW, Altemeier WA. Mechanical ventilation modulates Toll-like receptor-3-induced lung inflammation via a MyD88-dependent, TLR4-independent pathway: a controlled animal study. BMC Pulm Med. 2010;10:57. doi: 10.1186/1471-2466-10-57.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Dhanireddy S, Altemeier WA, Matute-Bello G, O’Mahony DS, Glenny RW, Martin TR, et al. Mechanical ventilation induces inflammation, lung injury, and extra-pulmonary organ dysfunction in experimental pneumonia. Lab Invest. 2006;86:790–9. doi: 10.1038/labinvest.3700440.CrossRefPubMedGoogle Scholar
  30. 30.
    Gurkan OU, O’Donnell C, Brower R, Ruckdeschel E, Becker PM. Differential effects of mechanical ventilatory strategy on lung injury and systemic organ inflammation in mice. Am J Physiol Lung Cell Mol Physiol. 2003;285:L710–8. doi: 10.1152/ajplung.00044.2003.CrossRefPubMedGoogle Scholar
  31. 31.
    Allen GB, Leclair T, Cloutier M, Thompson-Figueroa J, Bates JHT. The response to recruitment worsens with progression of lung injury and fibrin accumulation in a mouse model of acid aspiration. Am J Physiol Lung Cell Mol Physiol. 2007;292:L1580–9. doi: 10.1152/ajplung.00483.2006.CrossRefPubMedGoogle Scholar
  32. 32.
    Makena PS, Luellen CL, Balazs L, Ghosh MC, Parthasarathi K, Waters CM, et al. Preexposure to hyperoxia causes increased lung injury and epithelial apoptosis in mice ventilated with high tidal volumes. Am J Physiol Lung Cell Mol Physiol. 2010;299:L711–9. doi: 10.1152/ajplung.00072.2010.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2008;295:L379–99. doi: 10.1152/ajplung.00010.2008.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009;119:2898–913. doi: 10.1172/JCI36498.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Klaff LS, Gill SE, Wisse BE, Mittelsteadt K, Matute-Bello G, Chen P, et al. Lipopolysaccharide-induced lung injury is independent of serum vitamin d concentration. PLoS ONE. 2012;7:e49076. doi: 10.1371/journal.pone.0049076.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Skerrett SJ, Liggitt HD, Hajjar AM, Wilson CB. Cutting edge: myeloid differentiation factor 88 is essential for pulmonary host defense against Pseudomonas aeruginosa but not Staphylococcus aureus. J Immunol. 2004;172:3377–81.CrossRefPubMedGoogle Scholar
  37. 37.
    Tsai WC, Strieter RM, Zisman DA, Wilkowski JM, Bucknell KA, Chen GH, et al. Nitric oxide is required for effective innate immunity against Klebsiella pneumoniae. Infect Immun. 1997;65:1870–5.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Altemeier WA, Sinclair SE. Hyperoxia in the intensive care unit: why more is not always better. Current Opin Crit Care. 2007;13:73–8. doi: 10.1097/MCC.0b013e32801162cb.CrossRefGoogle Scholar
  39. 39.
    Lozon TI, Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS, Altemeier WA. PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2011;300:L422–9. doi: 10.1152/ajplung.00166.2010.CrossRefPubMedGoogle Scholar
  40. 40.
    Umezawa H. Bleomycin and other antitumor antibiotics of high molecular weight. Antimicrob Agents Chemother. 1965;5:1079–85.PubMedGoogle Scholar
  41. 41.
    Gasse P, Mary C, Guenon I, Noulin N, Charron S, Schnyder-Candrian S, et al. IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice. J Clin Invest. 2007;117:3786–99. doi: 10.1172/JCI32285.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Xu J, Mora A, Shim H, Stecenko A, Brigham KL, Rojas M. Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am J Respir Cell Mol Biol. 2007;37:291–9. doi: 10.1165/rcmb.2006-0187OC.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bundesmann MM, Wagner TE, Chow Y-H, Altemeier WA, Steinbach T, Schnapp LM. Role of urokinase plasminogen activator receptor-associated protein in mouse lung. Am J Respir Cell Mol Biol. 2012;46:233–9. doi: 10.1165/rcmb.2010-0485OC.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Das S, MacDonald K, Chang H-YS, Mitzner W. A simple method of mouse lung intubation. J Vis Exp. 2013; e50318. doi: 10.3791/50318.
  45. 45.
    Cai Y, Kimura S. Noninvasive intratracheal intubation to study the pathology and physiology of mouse lung. J Vis Exp. 2013; e50601. doi: 10.3791/50601.
  46. 46.
    Thomas JL, Dumouchel J, Li J, Magat J, Balitzer D, Bigby TD. Endotracheal intubation in mice via direct laryngoscopy using an otoscope. J Vis Exp. 2014;. doi: 10.3791/50269.Google Scholar
  47. 47.
    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. N Engl J Med. 2000;342:1301–8. doi: 10.1056/NEJM200005043421801.
  48. 48.
    O’Mahony DS, Liles WC, Altemeier WA, Dhanireddy S, Frevert CW, Liggitt D, et al. Mechanical ventilation interacts with endotoxemia to induce extrapulmonary organ dysfunction. Crit Care. 2006;10:R136. doi: 10.1186/cc5050.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Gharib SA, Liles WC, Matute-Bello G, Glenny RW, Martin TR, Altemeier WA. Computational identification of key biological modules and transcription factors in acute lung injury. Am J Respir Crit Care Med. 2006;173:653–8. doi: 10.1164/rccm.200509-1473OC.CrossRefPubMedGoogle Scholar
  50. 50.
    Gharib SA, Liles WC, Klaff LS, Altemeier WA. Noninjurious mechanical ventilation activates a proinflammatory transcriptional program in the lung. Physiol Genomics. 2009;37:239–48. doi: 10.1152/physiolgenomics.00027.2009.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Bomsztyk K, Mar D, An D, Sharifian R, Mikula M, Gharib SA, et al. Experimental acute lung injury induces multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction. Crit Care. 2015;19:225. doi: 10.1186/s13054-015-0943-4.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Gharib SA, Mar D, Bomsztyk K, Denisenko O, Dhanireddy S, Liles WC, et al. System-wide mapping of activated circuitry in experimental systemic inflammatory response syndrome. Shock. 2016;45:148–56. doi: 10.1097/SHK.0000000000000507.CrossRefPubMedGoogle Scholar
  53. 53.
    Oeckler RA, Lee W-Y, Park M-G, Kofler O, Rasmussen DL, Lee H-B, et al. Determinants of plasma membrane wounding by deforming stress. Am J Physiol Lung Cell Mol Physiol. 2010;299:L826–33. doi: 10.1152/ajplung.00217.2010.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Plataki M, Lee YD, Rasmussen DL, Hubmayr RD. Poloxamer 188 facilitates the repair of alveolus resident cells in ventilator-injured lungs. Am J Respir Crit Care Med. 2011;184:939–47. doi: 10.1164/rccm.201104-0647OC.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Hsia CCW, Hyde DM, Ochs M, Weibel ER, ATS/ERS Joint Task Force on Quantitative Assessment of Lung Structure. An official research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. Am J Respir Crit Care Med. 2010. p. 394–418. doi: 10.1164/rccm.200809-1522ST.
  56. 56.
    Moitra J, Sammani S, Garcia JGN. Re-evaluation of Evans Blue dye as a marker of albumin clearance in murine models of acute lung injury. Transl Res. 2007;150:253–65. doi: 10.1016/j.trsl.2007.03.013.CrossRefPubMedGoogle Scholar
  57. 57.
    Bates JHT. Pulmonary mechanics: a system identification perspective. Conf Proc IEEE Eng Med Biol Soc. 2009;1:170–2. doi: 10.1109/IEMBS.2009.5333302.Google Scholar
  58. 58.
    Foster WM, Walters DM, Longphre M, Macri K, Miller LM. Methodology for the measurement of mucociliary function in the mouse by scintigraphy. J Appl Physiol. 2001;90:1111–7.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • William A. Altemeier
    • 1
    Email author
  • Chi F. Hung
    • 1
  • Gustavo Matute-Bello
    • 1
  1. 1.Division of Pulmonary and Critical Care Medicine, Department of MedicineCenter for Lung Biology, University of WashingtonSeattleUSA

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