, Volume 196, Issue 5, pp 609–616 | Cite as

Inflammatory and Fibrinolytic System in Acute Respiratory Distress Syndrome

  • Mahesh Manjunath Gouda
  • Sadiya B. Shaikh
  • Yashodhar Prabhakar BhandaryEmail author


Acute respiratory distress syndrome (ARDS) is the most advanced form of acute lung injury (ALI). This is characterized by bilateral pulmonary infiltrates and severe hypoxemia. According to Berlin definition of ARDS, this is defined based on the timings, radiographic changes, edema formation, and severity on the PaO2/FiO2 ratio. During ARDS, the loss of integrity of the epithelium causes the septic shock. The degree of epithelial injury is the major prognostic marker of ARDS. In addition to this, inflammatory cell migration, fibro-proliferation, and activation of apoptosis also play an important role in the pathophysiology of ARDS. The alveolar epithelial cell is the prime target during injury where this cell either undergo apoptosis or epithelial–mesenchymal transition (EMT). Injury to the AECs triggers the changes in the DNA fragmentation and activation of certain apoptotic markers such as caspases at the same time some cells undergo biochemical changes and loses its epithelial morphology as well epithelial biomarkers and gain mesenchymal biomarkers and morphology. In both the cases, the fibrinolytic system plays an important role in maintaining the integrity of the disease process efficiently. This review highlights the research evidence of apoptosis and EMT in lung development, injury and its prognosis in ARDS thereby to develop an effective strategy for the treatment of ARDS.


Acute lung injury ARDS Apoptosis EMT 



The authors would like to thank Yenepoya Research Centre/Yenepoya University for providing the online library resources for writing this review article.

Compliance with Ethical Standards

Conflict of interest

Authors declare that they have no conflict of interest.


  1. 1.
    Matthay MA, Zemans RL (2011) The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol Mech Dis 6:147–163. CrossRefGoogle Scholar
  2. 2.
    Galani V, Tatsaki E, Bai M, Kitsoulis P, Lekka M, Nakos G, Kanavaros P (2010) The role of apoptosis in the pathophysiology of acute respiratory distress syndrome (ARDS): an up-to-date cell-specific review. Pathol Res Pract 206:145–150. CrossRefPubMedGoogle Scholar
  3. 3.
    Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349. CrossRefPubMedGoogle Scholar
  4. 4.
    Wiener-Kronish JP, Albertine KH, Matthay MA (1991) Differential responses of the endothelial and epithelial barriers of the lung in sheep to Escherichia coli endotoxin. J Clin Invest 88:864–875. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kurahashi K, Kajikawa O, Sawa T, Ohara M, Gropper MA, Frank DW, Martin TR, Wiener-Kronish JP (1999) Pathogenesis of septic shock in Pseudomonas aeruginosa pneumonia. J Clin Invest 104:743–750. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Matthay MA, Uchida T, Fang X (2002) Clinical acute lung injury and acute respiratory distress syndrome. Curr Treat Options Cardiovasc Med 4:139–149. CrossRefPubMedGoogle Scholar
  7. 7.
    Shetty S, Padijnayayveetil J, Tucker T, Stankowska D, Idell S (2008) The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability. Am J Physiol Lung Cell Mol Physiol 295:967–975. CrossRefGoogle Scholar
  8. 8.
    Bhandary YP, Shetty SK, Marudamuthu AS, Ji HL, Neuenschwander PF, Boggaram V, Morris GF, Fu J, Idell S, Shetty S (2013) Regulation of lung injury and fibrosis by p53-mediated changes in urokinase and plasminogen activator inhibitor-1. Am J Pathol 183:131–143. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bhandary YP, Shetty SK, Marudamuthu AS, Gyetko MR, Idell S, Gharaee-Kermani M, Shetty RS, Starcher BC, Shetty S (2011) Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system. Am J Physiol Lung Cell Mol Physiol 302:463–473. CrossRefGoogle Scholar
  10. 10.
    Han S, Mallampalli RK (2015) The acute respiratory distress syndrome: From mechanism to translation. J Immunol 194:855–860CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Watanabe R, Wada H, Watanabe Y, Sakakura M, Nakasaki T, Mori Y, Nishikawa M, Gabazza EC, Nobori T, Shiku H (2001) Activity and antigen levels of thrombin-activatable fibrinolysis inhibitor in plasma of patients with disseminated intravascular coagulation. Thromb Res 104:1–6CrossRefPubMedGoogle Scholar
  12. 12.
    Marudamuthu AS, Bhandary YP, Shetty SK, Gyetko MR, Idell S, Gharaee-Kermani M, Shetty RS, Starcher BC, Shetty S (2015) Role of the urokinase-fibrinolytic system in epithelial–mesenchymal transition during lung injury. Am J Pathol 185:55–68. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Sakthivel KM, Hariharan S (2017) Regulatory players of DNA damage repair mechanisms: role in cancer chemoresistance. Biomed Pharmacother 93:1238–12345. CrossRefPubMedGoogle Scholar
  14. 14.
    Mello SS, Attardi LD (2018) Deciphering p53 signaling in tumor suppression. Curr Opin Cell Biol 51:65–72. CrossRefPubMedGoogle Scholar
  15. 15.
    Marudamuthu AS, Shetty SK, Bhandary YP, Karandashova S, Thompson M, Sathish V, Florova G, Hogan TB, Pabelick CM, Prakash YS, Tsukasaki Y (2015) Plasminogen activator inhibitor-1 suppresses pro-fibrotic responses in fibroblasts from fibrotic lungs. J Biol Chem 290:9428–9441. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rubenfeld GD (2003) Epidemiology of acute lung injury. Crit Care Med 31:276–284. CrossRefGoogle Scholar
  17. 17.
    Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353:1685. CrossRefPubMedGoogle Scholar
  18. 18.
    MacCallum NS, Evans TW (2005) Epidemiology of acute lung injury. Curr Opin Crit Care 11:43CrossRefPubMedGoogle Scholar
  19. 19.
    Estenssoro E, Dubin A, Laffaire E, Canales H, Sáenz G, Moseinco M, Pozo M, Gómez A, Baredes N, Jannello G, Osatnik J (2002) Incidence, clinical course, and outcome in 217 patients with acute respiratory distress syndrome. Crit Care Med 30:2450. CrossRefPubMedGoogle Scholar
  20. 20.
    Brower RG, Lanken PN, MacIntyre N (2004) Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351:327. CrossRefPubMedGoogle Scholar
  21. 21.
    Villar J, Blanco J, Añón JM, Santos-Bouza A, Blanch L, Ambrós A, Gandía F, Carriedo D, Mosteiro F, Basaldúa S, Fernández RL (2011) The ALIEN study: incidence and outcome of acute respiratory distress syndrome in the era of lung protective ventilation. Intensiv Care Med 37:1932. CrossRefGoogle Scholar
  22. 22.
    Es Esteban A, Frutos-Vivar F, Muriel A, Ferguson ND, Peñuelas O, Abraira V, Raymondos K, Rios F, Nin N, Apezteguía C, Violi DA (2013) Evolution of mortality over time in patients receiving mechanical ventilation. Am J Respir Crit Care Med 188:220CrossRefGoogle Scholar
  23. 23.
    Wang CY, Calfee CS, Paul DW, Janz DR, May AK, Zhuo H, Bernard GR, Matthay MA, Ware LB, Kangelaris KN (2014) One-year mortality and predictors of death among hospital survivors of acute respiratory distress syndrome. Intensiv Care Med 40:388. CrossRefGoogle Scholar
  24. 24.
    Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, Van Haren F, Larsson A, McAuley DF, Ranieri M (2016) Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA 315:788. CrossRefPubMedGoogle Scholar
  25. 25.
    Siegel MD, Parsons PE, Finlay G (2016) Acute respiratory distress syndrome: prognosis and outcomes in adults. UpToDateGoogle Scholar
  26. 26.
    Montgomery AB, Stager MA, Carrico CJ, Hudson LD (1985) Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 132:485. CrossRefPubMedGoogle Scholar
  27. 27.
    Bersten AD, Edibam C, Hunt T, Moran J, Group TA (2002) Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 165:443–448. CrossRefPubMedGoogle Scholar
  28. 28.
    Ricard JD, Dreyfuss D, Saumon G (2001) Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal. Am J Respir Crit Care Med 163:1176–1180. CrossRefPubMedGoogle Scholar
  29. 29.
    Shaikh P (2011) Cytokines and their physiologic and pharmacologic functions in inflammation: a review. Int J Pharm Life Sci 11:1247–1263Google Scholar
  30. 30.
    Standiford TJ, Kunkel SL, Phan SH, Rollins BJ, Strieter RM (1991) Alveolar macrophage-derived cytokines induce monocyte chemoattractant protein-1 expression from human pulmonary type II-like epithelial cells. J Biol Chem 266:9912–9918PubMedGoogle Scholar
  31. 31.
    Selman M, Pardo A (2006) Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc 3:364–372. CrossRefPubMedGoogle Scholar
  32. 32.
    Crimi E, Slutsky AS (2004) Inflammation and the acute respiratory distress syndrome. Best Pract Res Clin Anaesthesiol 18:477–492. CrossRefPubMedGoogle Scholar
  33. 33.
    Gasse P, Riteau N, Vacher R, Michel ML, Fautrel A, Di Padova F, Fick L, Charron S, Lagente V, Eberl G, Le Bert M (2011) IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis. PLoS ONE 6:23185. CrossRefGoogle Scholar
  34. 34.
    Ge S, Hertel B, Susnik N, Rong S, Dittrich AM, Schmitt R, Haller H, von Vietinghoff S (2014) Interleukin 17 receptor A modulates monocyte subsets and macrophage generation in vivo. PLoS ONE 9:1–10. CrossRefGoogle Scholar
  35. 35.
    Cheng DS, Han W, Chen SM, Sherrill TP, Chont M, Park GY, Sheller JR, Polosukhin VV, Christman JW, Yull FE, Blackwell TS (2007) Airway epithelium controls lung inflammation and injury through the NF-κB pathway. J Immunol 178:6504–6513. CrossRefPubMedGoogle Scholar
  36. 36.
    Gouda MM, Prabhu A, Bhandary YP (2017) Curcumin alleviates IL-17A-mediated p53-PAI-1 expression in bleomycin-induced alveolar basal epithelial cells. J Cell Biochem 119:2222–2230. CrossRefPubMedGoogle Scholar
  37. 37.
    Coffill CR, Lee AP, Siau JW (2016) The p53–Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans. Genes Dev 30:281–292. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Luce JM (1998) Acute lung injury and the acute respiratory distress syndrome. Crit Care Med 26:369–376CrossRefPubMedGoogle Scholar
  39. 39.
    Cheng IW, Matthay MA (2003) Acute lung injury and the acute respiratory distress syndrome. Crit Care Clin 19:693–712. CrossRefPubMedGoogle Scholar
  40. 40.
    Wheeler AP, Bernard GR (2007) Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet 369:1553–1564. CrossRefPubMedGoogle Scholar
  41. 41.
    Matthay MA, Zimmerman GA (2005) Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319–327. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Staub NC (1981) Pulmonary edema due to increased microvascular permeability. Annu Rev Med 32:291–312CrossRefPubMedGoogle Scholar
  43. 43.
    Crosby LM, Waters CM (2010) Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 298:715–731. CrossRefGoogle Scholar
  44. 44.
    Matthay MA, Ware LB, Zimmerman GA (2012)The acute respiratory distress syndrome. J Clin Investig 122:2731. CrossRefPubMedGoogle Scholar
  45. 45.
    Kasper M, Barth K (2017) Potential contribution of alveolar epithelial type I cells to pulmonary fibrosis. Biosci Rep 37:6. CrossRefGoogle Scholar
  46. 46.
    Matthay MA, Wiener-Kronish P (1990) Intact epithelial barrier function is critical for the resolution of alveolar edema in humans1-3. Am Rev Respir Dis 142:1250–1257CrossRefPubMedGoogle Scholar
  47. 47.
    Matthay MA, Zimmerman GA (2005) Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319–327. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Su X, Johansen M, Looney MR, Brown EJ, Matthay MA (2008) CD47 deficiency protects mice from lipopolysaccharide-induced acute lung injury and Escherichia coli pneumonia. J Immunol 180:6947–6953. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Zemans RL, Colgan SP, Downey GP (2009) Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury. Am J Respir Cell Mol Biol 40:519–535. CrossRefPubMedGoogle Scholar
  50. 50.
    Bhandari V, Choo-Wing R, Lee CG, Zhu Z, Nedrelow JH, Chupp GL, Zhang X, Matthay MA, Ware LB, Homer RJ, Lee PJ (2006) Hyperoxia causes angiopoietin 2-mediated acute lung injury and necrotic cell death. Nat Med 12:1286–1293. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Bachofen M, Weibel ER (1977) Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicemia. Am Rev Respir Dis 116:589–615. CrossRefPubMedGoogle Scholar
  52. 52.
    Bardales RH, Xie SS, Schaefer RF, Hsu SM. Apoptosis is a major pathway responsible for the resolution of type II pneumocytes in acute lung injury. Am J Pathol 149: 845–852Google Scholar
  53. 53.
    Guinee D Jr, Brambilla E, Fleming M, Hayashi T, Rahn M, Koss M, Ferrans V, Travis W (1997) The potential role of BAX and BCL-2 expression in diffuse alveolar damage. Am J Pathol 151:999–1007PubMedPubMedCentralGoogle Scholar
  54. 54.
    Lee WL, Downey GP (2001) Neutrophil activation and acute lung injury. Curr Opin Crit Care 7:1–7CrossRefPubMedGoogle Scholar
  55. 55.
    Kawasaki M, Kuwano K, Hagimoto N, Matsuba T, Kunitake R, Tanaka T, Maeyama T, Hara N (2000) Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor. Am J Pathol 157:597–603. CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Albertine KH, Soulier MF, Wang Z, Ishizaka A, Hashimoto S, Zimmerman GA, Matthay MA, Ware LB (2002) Fas and fas ligand are up-regulated in pulmonary edema fluid and lung tissue of patients with acute lung injury and the acute respiratory distress syndrome. Am J Pathol 161:1783–1796. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Tanaka M, Itai T, Adachi M, Nagata S (1998) Downregulation of Fas ligand by shedding. Nat Med 4:31–36. CrossRefPubMedGoogle Scholar
  58. 58.
    Fine AL, Anderson NL, Rothstein TL, Williams MC, Gochuico BR (1997) Fas expression in pulmonary alveolar type II cells. Am J Physiol 273:L64–L71. CrossRefPubMedGoogle Scholar
  59. 59.
    Matute-Bello G, Winn RK, Jonas M, Chi EY, Martin TR, Liles WC (2001) Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation. Am J Pathol 158:153–161. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Martin TR, Nakamura M, Matute-Bello G (2003) The role of apoptosis in acute lung injury. Crit Care Med 31:S184–S188. CrossRefPubMedGoogle Scholar
  61. 61.
    Hay J, Shahzeidi S, Laurent G (1991) Mechanisms of bleomycin-induced lung damage. Arch Toxicol 65:81–94CrossRefPubMedGoogle Scholar
  62. 62.
    Hagimoto N, Kuwano K, Kawasaki M, Yoshimi M, Kaneko Y, Kunitake R, Maeyama T, Tanaka T, Hara N (1999) Induction of interleukin-8 secretion and apoptosis in bronchiolar epithelial cells by fas ligation. Am J Respir Cell Mol Biol 21:436–445. CrossRefPubMedGoogle Scholar
  63. 63.
    Kalluri R, Neilson EG (2003) Epithelial mesenchymal transition and its implications for fibrosis. J Clin Invest 112:1776–1784. CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Zeisberg M, Neilson EG (2009) Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119:1429–1437. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Potenta S, Zeisberg EG, Kalluri R (2008) The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 99:1375–1379. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG (2007) Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13:952–961. CrossRefPubMedGoogle Scholar
  67. 67.
    Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R (2007) Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282:23337–23347. CrossRefPubMedGoogle Scholar
  68. 68.
    Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA (2006) Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 103:13180–13185. CrossRefPubMedGoogle Scholar
  69. 69.
    Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14:818–829. CrossRefPubMedGoogle Scholar
  70. 70.
    Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454. CrossRefPubMedGoogle Scholar
  71. 71.
    Fidler IJ, Poste G (2008) The “seed and soil” hypothesis revisited. Lancet Oncol 9:808. CrossRefPubMedGoogle Scholar
  72. 72.
    Brabletz T, Jung A, Reu S, Porzner M, Hlubek F, Kunz-Schughart LA, Knuechel R, Kirchner T(2001) Variable beta-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc Natl Acad Sci USA 98:10356–10361. CrossRefPubMedGoogle Scholar
  73. 73.
    Heise RL, Stober V, Cheluvaraju C, Hollingsworth JW, Garantziotis S (2011) Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J Biol Chem 286:17435–17444. CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Li LF, Liu YY, Kao KC, Wu CT, Chang CH, Hung CY, Yang CT (2014) Mechanical ventilation augments bleomycin-induced epithelial-mesenchymal transition through the Src pathway. Lab Invest 94:1017–1029. CrossRefPubMedGoogle Scholar
  75. 75.
    Li LF, Lee CS, Lin CW, Chen NH, Chuang LP, Hung CY, Liu YY (2017) Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway. PLoS ONE 12:0172571. CrossRefGoogle Scholar
  76. 76.
    Chen Q, Luo AA, Qiu H, Han B, Ko BH, Slutsky AS, Zhang H (2014) Monocyte interaction accelerates HCl-induced lung epithelial remodeling. BMC Pulm Med 14:135. CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Zhang YQ, Liu YJ, Mao YF, Dong WW, Zhu XY, Jiang L (2015) Resveratrol ameliorates lipopolysaccharide-induced epithelial mesenchymal transition and pulmonary fibrosis through suppression of oxidative stress and transforming growth factor-β1 signaling. Clin Nutr 34:752–760. CrossRefPubMedGoogle Scholar
  78. 78.
    Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102:8204–8209. CrossRefPubMedGoogle Scholar
  79. 79.
    Wang Z, Jiang Y, Guan D, Li J, Yin H, Pan Y, Xie D, Chen Y (2013) Critical roles of p53 in epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma cells. PLoS ONE 8:72846. CrossRefGoogle Scholar
  80. 80.
    Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, Yu WH, Rehman SK, Hsu JL, Lee HH, Liu M (2011) p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol 13:317CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 353:1711–1723CrossRefPubMedGoogle Scholar
  82. 82.
    Nakayama S, Yokote T, Kobayashi K, Hirata Y, Akioka T, Hara S, Miyoshi T, Takubo T, Tsuji M, Hanafusa T (2008) Successful therapy with high-dose steroids and cyclosporin in lenograstim-induced acute respiratory distress syndrome. Respir Med CME 1:188–192CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Yenepoya Research CentreYenepoya (Deemed to be University)MangaloreIndia

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