ABSTRACT

ARDS is a clinical syndrome secondary to acute lung injury, which leads to damage of the alveolar pulmonary capillary membrane, with increased permeability. The clinical description of the syndrome has been discussed in several reviews; however, it’s still difficult to predict the clinical behavior that patients will have, some of them decay rapidly while others quickly achieve their improvement. Knowledge of the molecular aspects that regulate physiological processes will be discussed in this review, in order to identify possible genetic markers, predictive value to identify patients who may be more susceptible to develop ARDS, or a patient group more likely to have a better response to a particular treatment and the prognosis of individual patients.

KEYWORDS

Acute lung injury, respiratory distress syndrome, biomarkers, treatment outcome.

REFERENCES

1. Donahoe M. Acute respiratory distress syndrome: A clinical review. Pulm Circ 2011;1(2):192-211. doi: 10.4103/2045-8932.83454.

2. Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. Chest 2007;131(2):554-562.

3. Walkey AJ, Summer R, Ho V, Alkana P. Acute respiratory distress syndrome: epidemiology and management approaches. Clin Epidemiol 2012;4:159-169. doi: 10.2147/CLEP.S28800.

4. ARDS Definition Task Force; Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin definition. JAMA 2012;307(23):2526-2533. doi: 10.1001/jama.2012.5669.

5. Fanelli V, Vlachou A, Ghannadian S, Simonetti U, Slutsky AS, Zhang H. Acute respiratory distress syndrome: new definition, current and future therapeutic options. J Thorac Dis 2013;5(3):326-334. doi: 10.3978/j.issn.2072-1439.2013.04.05.

6. Pierrakos C, Karanikolas M, Scolletta S, Karamouzos V, Velissaris D. Acute respiratory distress syndrome: pathophysiology and therapeutic options. J Clin Med Res 2012;4(1):7-16. doi: 10.4021/jocmr761w.

7. Nader ND, McQuiller PS, Raghavendran K, Spengler RN, Knight PR. The role of alveolar macrophages in the pathogenesis of aspiration pneumonitis. Immunol Invest 2007;36(4):457-471.

8. Ware LB. Pathophysiology of acute lung injury and the acute respiratory distress syndrome. Semin Respir Crit Care Med 2006;27(4):337-349.

9. Teuffel O, Ethier MC, Beyene J, Sung L. Association between tumor necrosis factor-alpha promoter -308 A/G polymorphism and susceptibility to sepsis and sepsis mortality: a systematic review and meta-analysis. Crit Care Med 2010;38(1):276-282. doi: 10.1097/CCM.0b013e3181b42af0.

10. Gong MN, Zhou W, Williams PL, et al. -308GA and TNFB polymorphisms in acute respiratory distress syndrome. Eur Respir J 2005;26(3):382-389.

11. Parsons PE, Eisner MD, Thompson BT, et al.; NHLBI Acute Respiratory Distress Syndrome Clinical Trials Network. Lower tidal volume ventilation and plasma cytokine markers of inflammation in patients with acute lung injury. Crit Care Med 2005;33(1):1-6.

12. Olman MA, White KE, Ware LB, et al. Pulmonary edema fluid from patients with early lung injury stimulates fibroblast proliferation through IL-1 beta-induced IL-6 expression. J Immunol 2004;172(4):2668-2677.

13. Ganter MT, Roux J, Miyazawa B, et al. Interleukin-1beta causes acute lung injury via alphavbeta5 and alphavbeta6 integrin-dependent mechanisms. Circ Res 2008;102(7):804-812. doi: 10.1161/CIRCRESAHA.107.161067.

14. Park WY, Goodman RB, Steinberg KP, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001;164(10 Pt 1):1896-1903.

15. Meyer NJ, Feng R, Li M, et al. IL1RN coding variant is associated with lower risk of acute respiratory distress syndrome and increased plasma IL-1 receptor antagonist. Am J Respir Crit Care Med 2013;187(9):950-959. doi: 10.1164/rccm.201208-1501OC.

16. McClintock D, Zhuo H, Wickersham N, Matthay MA, Ware LB. Biomarkers of inflammation, coagulation and fibrinolysis predict mortality in acute lung injury. Crit Care 2008;12(2):R41. doi: 10.1186/cc6846.

17. Lin WC, Lin CF, Chen CL, Chen CW, Lin YS. Prediction of outcome in patients with acute respiratory distress syndrome by bronchoalveolar lavage inflammatory mediators. Exp Biol Med (Maywood) 2010;235(1):57-65. doi: 10.1258/ebm.2009.009256.

18. Flores C, Ma SF, Maresso K, Wade MS, Villar J, Garcia JG. IL6 gene-wide haplotype is associated with susceptibility to acute lung injury. Transl Res 2008;152(1):11-17. doi: 10.1016/j.trsl.2008.05.006.

19. Mukaida N. Pathophysiological roles of interleukin-8/CXCL8 in pulmonary diseases. Am J Physiol Lung Cell Mol Physiol 2003;284(4):L566-577.

20. Schottelius AJ, Mayo MW, Sartor RB, Baldwin AS Jr. Interleukin-10 signaling blocks inhibitor of kappa B kinase activity and nuclear factor kappa B DNA binding. J Biol Chem 1999;274(45):31868-31874.

21. Gong MN, Thompson BT, Williams PL, et al. Interleukin-10 polymorphism in position -1082 and acute respiratory distress syndrome. Eur Respir J 2006;27(4):674-681.

22. Cross LJ, Matthay MA. Biomarkers in acute lung injury: insights into the pathogenesis of acute lung injury. Crit Care Clin 2011;27(2):355-377. doi: 10.1016/j.ccc.2010.12.005.

23. Ito Y, Mason RJ. The effect of interleukin-13 (IL-13) and interferon-γ (IFN-γ) on expression of surfactant proteins in adult human alveolar type II cells in vitro. Respir Res 2010;11:157. doi: 10.1186/1465-9921-11-157.

24. Bajwa EK, Khan UA, Januzzi JL, Gong MN, Thompson BT, Christiani DC. Plasma C-reactive protein levels are associated with improved outcome in ARDS. Chest 2009;136(2):471-480. doi: 10.1378/chest.08-2413.

25. Tseng JS, Chan MC, Hsu JY, Kuo BI, Wu CL. Procalcitonin is a valuable prognostic marker in ARDS caused by community-acquired pneumonia. Respirology 2008;13(4):505-509. doi: 10.1111/j.1440-1843.2008.01293.x.

26. Turner MW. The role of mannose-binding lectin in health and disease. Mol Immunol 2003;40(7):423-429.

27. Garred P, Pressler T, Madsen HO, et al. Association of mannose-binding lectin gene heterogeneity with severity of lung disease and survival in cystic fibrosis. J Clin Invest 1999;104(4):431-437.

28. Gao L, Flores C, Fan-Ma S, et al. Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations. Transl Res 2007;150(1):18-29.

29. Luk T, Malam Z, Marshall JC. Pre-B cell colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity. J Leukoc Biol 2008;83(84):804-816. doi: 10.1189/jlb.0807581.

30. Bajwa EK, Yu CL, Gong MN, Thompson BT, Christiani DC. Pre-B-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome. Crit Care Med 2007;35(5):1290-1295.

31. Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-kappa B in pulmonary diseases. Chest 2000;117(5):1482-1487.

32. Adamzik M, Frey UH, Rieman K, et al. Insertion/deletion polymorphism in the promoter of NFKB1 influences severity but not mortality of acute respiratory distress syndrome. Intensive Care Med 2007;33(7):1199-1203.

33. Zhai R, Zhou W, Gong MN, et al. Inhibitor kappa B-alpha haplotype GTC is associated with susceptibility to acute respiratory distress syndrome in Caucasians. Crit Care Med 2007;35(3):893-898.

34. Madtes DK, Rubenfeld G, Klima LD, et al. Elevated transforming growth factor-alpha levels in bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 1998;158(2):424-430.

35. Peters DM, Vadász I, Wujak L, et al. TGF-β directs trafficking of the epithelial sodium channel ENaC which has implications for ion and fluid transport in acute lung injury. Proc Natl Acad Sci USA 2014;111(3):E374-383. doi: 10.1073/pnas.1306798111

36. Frank JA, Matthay MA. TGF-β and lung fluid balance in ARDS. Proc Natl Acad Sci USA 2014;111(3):885-886. doi: 10.1073/pnas.1322478111.

37. Medford AR, Millar AB. Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): paradox or paradigm? Thorax 2006;61(7):621-626.

38. Zhai R, Gong MN, Zhou W, et al. Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS. Thorax 2007;62(8):718-722.

39. Fiedler U, Scharpfenecker M, Koidl S, et al. The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood 2004;103(11):4150-4156.

40. Gallagher DC, Parikh SM, Balonov K, et al. Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome. Shock 2008;29(6):656-661.

41. Meyer NJ, Li M, Feng R, et al. ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. Am J Respir Crit Care Med 2011;183(10):1344-1353. doi: 10.1164/rccm.201005-0701OC.

42. Marshall RP, Webb S, Bellingan GJ, et al. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 2002;166(5):646-650.

43. Matsuda A, Kishi T, Jacob A, Aziz M, Wang P. Association between insertion/deletion polymorphism in angiotensin-converting enzyme gene and acute lung injury/acute respiratory distress syndrome: a meta-analysis. BMC Med Genet 2012;13:76.

44. Imai Y, Kuba K, Penninger JM. Angiotensin-converting enzyme 2 in acute respiratory distress syndrome. Cell Mol Life Sci 2007;64(15):2006-2012.

45. Wösten-van Asperen RM, Bos AP, Bem RA, et al. Imbalance between pulmonary angiotensin-converting enzyme and angiotensin-converting enzyme 2 activity in acute respiratory distress syndrome. Pediatr Crit Care Med 2013;14(9):e438-441. doi: 10.1097/PCC.0b013e3182a55735.

46. Christie JD, Ma SF, Aplenc R, et al. Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma. Crit Care Med 2008;36(10):2794-2800.

47. Gao L, Grant A, Halder I, et al. Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. Am J Respir Cell Mol Biol 2006;34(4):487-495.

48. McCormack FX, Gibbons R, Ward SR, Kuzmenko A, Wu H, Deepe GS Jr. Macrophage-independent fungicidal action of the pulmonary collections. J Biol Chem 2003;278(38):36250-36256.

49. Eisner MD, Parsons P, Matthay MA, Ware L, Greene K; Acute Respiratory Distress Syndrome Network. Plasma surfactant protein levels and clinical outcomes in patients with acute lung injury. Thorax 2003;58(11):983-988.

50. Gong MN, Wei Z, Xu LL, Miller DP, Thompson BT, Christiani DC. Polymorphism in the surfactant protein-B gene, gender, and the risk of direct pulmonary injury and ARDS. Chest 2004;125(1):203-211.

51. Quasney MW, Waterer GW, Dahmer MK, et al. Association between surfactant protein B + 1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia. Crit Care Med 2004;32(5):1115-1119.

52. Sato H, Callister ME, Mumby S, et al. KL-6 levels are elevated in plasma from patients with acute respiratory distress syndrome. Eur Respir J 2004;23(1):142-145.

53. Ishizaka A, Matsuda T, Albertine KH, et al. Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2004;286(6):L1088-1094.

54. Ménoret A, Kumar S, Vella AT. Cytochrome b5 and cytokeratin 17 are biomarkers in bronchoalveolar fluid signifying onset of acute lung injury. PLoS One 2012;7(7):e40184. doi: 10.1371/journal.pone.0040184.

55. Creagh-Brown BC, Quinlan GJ, Evans TW, Burke-Gaffney A. The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target? Intensive Care Med 2010;36(19):1644-1656. doi: 10.1007/s00134-010-1952-z.

56. Fremont RD, Koyama T, Calfee CS, et al. Acute lung injury in patients with traumatic injuries: utility of a panel of biomarkers for diagnosis and pathogenesis. J Trauma 2010;68:1121-1127. doi: 10.1097/TA.0b013e3181c40728.

57. Determann RM, Millo JL, Waddy S, Lutter R, Garrard CS, Schultz MJ. Plasma CC16 levels are associated with development of ALI/ARDS in patients with ventilator-associated pneumonia: a retrospective observational study. BMC Pulm Med 2009;9:49. doi: 10.1186/1471-2466-9-49.

58. Kropski JA, Fremont RD, Calfee CS, Ware LB. Clara cell protein (CC16), a marker of lung epithelial injury, is decreased in plasma and pulmonary edema fluid from patients with acute lung injury. Chest 2009;135(6):1440-1447. doi: 10.1378/chest.08-2465.

59. Frerking I, Sengler C, Günther A, et al. Evaluation of the -26G > A CC16 polymorphism in acute respiratory distress syndrome. Crit Care Med 2005;33(10):2404-2406.

60. Wang Z, Beach D, Su L, Zhai R, Christiani DC. A genome-wide expression analysis in blood identifies pre-elafin as a biomarker in ARDS. Am J Respir Cell Mol Biol 2008;38(6):724-732. doi: 10.1165/rcmb.2007-0354OC.

61. Wang Z, Chen F, Zhai R, et al. Plasma neutrophil elastase and elafin imbalance is associated with acute respiratory distress syndrome (ARDS) development. PLoS One 2009;4(2):e4380. doi: 10.1371/journal.pone.0004380.

62. Tejera P, Wang Z, Zhai R, et al. Genetic polymorphisms of peptidase inhibitor 3 (elafin) are associated with acute respiratory distress syndrome. Am J Respir Cell Mol Biol 2009;41(6):696-704. doi: 10.1165/rcmb.2008-0410OC.

63. Arcaroli JJ, Hokanson JE, Abraham E, et al. Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality. Am J Respir Crit Care Med 2009;179(2):105-112. doi: 10.1164/rccm.200710-1566OC.

64. Fredenburgh LE, Baron RM, Carvajal IM, et al. Absence of heme oxygenase-1 expression in the lung parenchyma exacerbates endotoxin-induced acute lung injury and decreases surfactant protein-B levels. Cell Mol Biol (Noisy-le-grand) 2005;51(5):513-520.

65. Fredenburgh LE, Perrella MA, Mitsialis SA. The role of heme oxygenase-1 in pulmonary disease. Am J Respir Cell Mol Biol 2007;36(2):158-165.

66. Adamzik M, Frey U, Sixt S, et al. ACE I/D but not AGT (-6)A/G polymorphism is a risk factor for mortality in ARDS. Eur Respir J 2007;29(3):482-488.

67. Mumby S, Upton RL, Chen Y, et al. Lung heme oxygenase-1 is elevated in acute respiratory distress syndrome. Crit Care Med 2004;32(5):1130-1135.

68. Wang G, Han D, Zhang Y, et al. A novel hypothesis: up-regulation of HO-1 by activation of PPARγ inhibits HMGB1-RAGE signaling pathway and ameliorates the development of ALI/ARDS. J Thorac Dis 2013;5(5):706-710. doi: 10.3978/j.issn.2072-1439.2013.08.69.

69. Exner M, Minar E, Wagner O, Schillinger M. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med 2004;37(8):1097-1104.

70. Sheu CC, Zhai R, Wang Z, et al. Heme oxygenase-1 microsatellite polymorphism and haplotypes are associated with the development of acute respiratory distress syndrome. Intensive Care Med 2009;35(8):1343-1351. doi: 10.1007/s00134-009-1504-6.

71. Flori HR, Ware LB, Milet M, Matthay MA. Early elevation of plasma von Willebrand factor antigen in pediatric acute lung injury is associated with an increased risk of death and prolonged mechanical ventilation. Pediatr Crit Care Med 2007;8(2):96-101.

72. Ware LB, Fang X, Matthay MA. Protein C and thrombomodulin in human acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003;285(3):L514-L521.

73. Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GR. Low levels of protein C are associated with poor outcome in severe sepsis. Chest 2001;120(3):915-922.

74. Adamzik M, Frey UH, Riemann K, et al. Factor V Leiden mutation is associated with improved 30-day survival in patients with acute respiratory distress syndrome. Crit Care Med 2008;36(6):1776-1779. doi: 10.1097/CCM.0b013e318174373d.

75. Benfield T, Ejrnaes K, Juul K, et al. Influence of factor V Leiden on susceptibility to and outcome from critical illness: a genetic association study. Crit Care 2010;14(2):R28. doi: 10.1186/cc8899.

76. Ware LB, Conner ER, Matthay MA. von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury. Crit Care Med 2001;29(12):2325-2331.

77. Ware LB, Eisner MD, Thompson BT, Parsons PE, Matthay MA. Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury. Am J Respir Crit Care Med 2004;170(7):766-772.

78. Sapru A, Curley MA, Brady S, Matthay MA, Flori H. Elevated PAI-1 is associated with poor clinical outcomes in pediatric patients with acute lung injury. Intensive Care Med 2010;36(1):157-163. doi: 10.1007/s00134-009-1690-2.

79. Arcaroli J, Sankoff J, Liu N, Allison DB, Maloney J, Abraham E. Association between urokinase haplotypes and outcome from infection-associated acute lung injury. Intensive Care Med 2008;34(2):300-307.

80. Prabhakaran P, Ware LB, White KE, Cross MT, Matthay MA, Olman MA. Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003;285(1):L20-28.

81. Ware LB, Matthay MA, Parsons PE, Thompson BT, Januzzi JL, Eisner MD; National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome Clinical Trials Network. Pathogenetic and prognostic significance of altered coagulation and fibrinolysis in acute lung injury/acute respiratory distress syndrome. Crit Care Med 2007;35(8):1821-1828.