The Complex Interaction between Sepsis and Lung Injury

  • R. Herrero
  • I. Martin-Loeches
  • A. Artigas
Part of the Annual Update in Intensive Care and Emergency Medicine book series (AUICEM, volume 2012)


Sepsis is a major cause of acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS) [1, 2]. In addition, sepsis frequently complicates the clinical course of patients with ALI of other etiologies. The most common cause of ALI/ARDS is pneumonia (bacterial, viral or fungal), followed by severe sepsis from pulmonary or non-pulmonary infections [2, 3]. Sepsis accounts for approximately 25 to 40 % of cases of ALI/ARDS, the risk of ALI being especially high in the presence of intense systemic inflammatory response, shock and multiorgan dysfunction. The association of sepsis with disseminated intravascular coagulation (DIC) also increases the risk of progression to ALI/ARDS [3, 4].


Lung Injury Severe Sepsis Acute Lung Injury Acute Respiratory Distress Syndrome Disseminate Intravascular Coagulation 
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  1. 1.
    Gajic O, Dabbagh O, Park PK, et al (2011) Early identification of patients at Risk of acute lung injury: evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med 183: 462–470PubMedCrossRefGoogle Scholar
  2. 2.
    Hudson LD, Steinberg KP (1999) Epidemiology of acute lung injury and ARDS. Chest 116: 74S–82SPubMedCrossRefGoogle Scholar
  3. 3.
    Iscimen R, Cartin-Ceba R, Yilmaz M, et al (2008) Risk factors for the development of acute lung injury in patients with septic shock: an observational cohort study. Crit Care Med 36: 1518–1522PubMedCrossRefGoogle Scholar
  4. 4.
    Fein AM, Calalang-Colucci MG (2000) Acute lung injury and acute Respiratory distress syndrome in sepsis and septic shock. Crit Care Clin 16: 289–317PubMedCrossRefGoogle Scholar
  5. 5.
    Dellinger RP, Levy MM, Carlet JM, et al (2008) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Intensive Care Med 34: 17–60PubMedCrossRefGoogle Scholar
  6. 6.
    Suarez D, Ferrer R, Artigas A, Azkarate I, et al (2011) Cost-effectiveness of the Surviving Sepsis Campaign protocol for severe sepsis: a prospective nation-wide study in Spain. Intensive Care Med 37: 444–452PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrer R, Artigas A, Suarez D, et al (2009) Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. Am J Respir Crit Care Med 180: 861–866PubMedCrossRefGoogle Scholar
  8. 8.
    Ferrer R, Artigas A, Levy MM, et al (2008) Improvement in process of care and outcome after a multicenter severe sepsis educational program in Spain. JAMA 299: 2294–2303PubMedCrossRefGoogle Scholar
  9. 9.
    Sheu CC, Gong MN, Zhai R, et al (2010) Clinical characteristics and outcomes of sepsisrelated vs non-sepsis-related ARDS. Chest 138: 559–567PubMedCrossRefGoogle Scholar
  10. 10.
    Ware LB, Matthay MA (2000) The acute Respiratory distress syndrome. N Engl J Med 342: 1334–1349PubMedCrossRefGoogle Scholar
  11. 11.
    Martin TR, Rubenfeld GD, Ruzinski JT, et al (1997) Relationship between soluble CD14, lipopolysaccharide binding protein, and the alveolar inflammatory Response in patients with acute Respiratory distress syndrome. Am J Respir Crit Care Med 155: 937–944PubMedCrossRefGoogle Scholar
  12. 12.
    Martin TR (2000) Recognition of bacterial endotoxin in the lungs. Am J Respir Cell Mol Biol 23: 128–132PubMedCrossRefGoogle Scholar
  13. 13.
    Matute-Bello G, Winn RK, Martin TR, Liles WC (2004) Sustained lipopolysaccharideinduced lung inflammation in mice is attenuated by functional deficiency of the Fas/Fas ligand system. Clin Diagn Lab Immunol 11: 358–361PubMedGoogle Scholar
  14. 14.
    Perl M, Chung CS, Lomas-Neira J, et al (2005) Silencing of Fas, but not caspase-8, in lung epithelial cells ameliorates pulmonary apoptosis, inflammation, and neutrophil influx after hemorrhagic shock and sepsis. Am J Pathol 167: 1545–1559PubMedCrossRefGoogle Scholar
  15. 15.
    Kudoh I, Wiener-Kronish JP, Hashimoto S, Pittet JF, Frank D (1994) Exoproduct secretions of Pseudomonas aeruginosa strains influence severity of alveolar epithelial injury. Am J Physiol 267: L551–556PubMedGoogle Scholar
  16. 16.
    Brigham KL, Woolverton WC, Blake LH, Staub NC (1974) Increased sheep lung vascular permeability caused by pseudomonas bacteremia. J Clin Invest 54: 792–804PubMedCrossRefGoogle Scholar
  17. 17.
    Altemeier WA, Matute-Bello G, Frevert CW, et al (2004) Mechanical ventilation with moderate tidal volumes synergistically increases lung cytokine Response to systemic endotoxin. Am J Physiol Lung Cell Mol Physiol 287: L533–542PubMedCrossRefGoogle Scholar
  18. 18.
    Smith LS, Gharib SA, Frevert CW, Martin TR (2010) Effects of age on the synergistic interactions between lipopolysaccharide and mechanical ventilation in mice. Am J Respir Cell Mol Biol 43: 475–486PubMedCrossRefGoogle Scholar
  19. 19.
    Kurahashi K, Ota S, Nakamura K, et al (2004) Effect of lung-protective ventilation on severe Pseudomonas aeruginosa pneumonia and sepsis in Rats. Am J Physiol Lung Cell Mol Physiol 287: L402–410PubMedCrossRefGoogle Scholar
  20. 20.
    Lipke AB, Matute-Bello G, Herrero R, et al (2010) Febrile-range hyperthermia augments lipopolysaccharide-induced lung injury by a mechanism of enhanced alveolar epithelial apoptosis. J Immunol 184: 3801–3813PubMedCrossRefGoogle Scholar
  21. 21.
    Faure E, Equils O, Sieling PA, et al (2000) Bacterial lipopolysaccharide activates NF-kappaB through toll-like Receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem 275: 11058–11063PubMedCrossRefGoogle Scholar
  22. 22.
    Seki H, Tasaka S, Fukunaga K, et al (2010) Effect of Toll-like Receptor 4 inhibitor on LPSinduced lung injury. Inflamm Res 59: 837–845PubMedCrossRefGoogle Scholar
  23. 23.
    Reddy AJ, Kleeberger SR (2009) Genetic polymorphisms associated with acute lung injury. Pharmacogenomics 10: 1527–1539PubMedCrossRefGoogle Scholar
  24. 24.
    Monchi M, Bellenfant F, Cariou A, et al (1998) Early predictive factors of survival in the acute Respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med 158: 1076–1081PubMedCrossRefGoogle Scholar
  25. 25.
    Martin TR (2002) Neutrophils and lung injury: getting it Right. J Clin Invest 110: 1603–1605PubMedGoogle Scholar
  26. 26.
    Pittet JF, Mackersie RC, Martin TR, Matthay MA (1997) Biological markers of acute lung injury: prognostic and pathogenetic significance. Am J Respir Crit Care Med 155: 1187–1205PubMedCrossRefGoogle Scholar
  27. 27.
    Moss M, Gillespie MK, Ackerson L, Moore FA, Moore EE, Parsons PE (1996) Endothelial cell activity varies in patients at Risk for the adult Respiratory distress syndrome. Crit Care Med 24: 1782–1786PubMedCrossRefGoogle Scholar
  28. 28.
    Li Z, Yang F, Dunn S, Gross AK, Smyth SS (2011) Platelets as immune mediators: their Role in host defense Responses and sepsis. Thromb Res 127: 184–188PubMedCrossRefGoogle Scholar
  29. 29.
    Venet F, Chung CS, Huang X, Lomas-Neira J, Chen Y, Ayala A (2009) Lymphocytes in the development of lung inflammation: a Role for Regulatory CD4+ T cells in indirect pulmonary lung injury. J Immunol 183: 3472–3480PubMedCrossRefGoogle Scholar
  30. 30.
    Martin C, Boisson C, Haccoun M, Thomachot L, Mege JL (1997) Patterns of cytokine evolution (tumor necrosis factor-alpha and interleukin-6) after septic shock, hemorrhagic shock, and severe trauma. Crit Care Med 25: 1813–1819PubMedCrossRefGoogle Scholar
  31. 31.
    Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A (1995) Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest 108: 1303–1314PubMedCrossRefGoogle Scholar
  32. 32.
    Welty-Wolf KE, Carraway MS, Ortel TL, Piantadosi CA (2002) Coagulation and inflammation in acute lung injury. Thromb Haemost 88: 17–25PubMedGoogle Scholar
  33. 33.
    Matthay MA, Zemans RL (2011) The acute Respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol 6: 147–163PubMedCrossRefGoogle Scholar
  34. 34.
    Miller DL, Welty-Wolf K, Carraway MS, et al (2002) Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine Release after intratracheal lipopolysaccharide. Am J Respir Cell Mol Biol 26: 650–658PubMedCrossRefGoogle Scholar
  35. 35.
    Kitamura Y, Hashimoto S, Mizuta N, et al (2001) Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice. Am J Respir Crit Care Med 163: 762–769PubMedCrossRefGoogle Scholar
  36. 36.
    Matute-Bello G, Liles WC, Steinberg KP, et al (1999) Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS). J Immunol 163: 2217–2225PubMedGoogle Scholar
  37. 37.
    Albertine KH, Soulier MF, Wang Z, et al (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: 1783–1796PubMedCrossRefGoogle Scholar
  38. 38.
    Hashimoto S, Kobayashi A, Kooguchi K, Kitamura Y, Onodera H, Nakajima H (2000) Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. Am J Respir Crit Care Med 161: 237–243PubMedCrossRefGoogle Scholar
  39. 39.
    Tateda K, Deng JC, Moore TA, et al (2003) Hyperoxia mediates acute lung injury and increased lethality in murine Legionella pneumonia: the Role of apoptosis. J Immunol 170: 4209–4216PubMedGoogle Scholar
  40. 40.
    Liu L, Qiu HB, Yang Y, Wang L, Ding HM, Li HP (2009) Losartan, an antagonist of AT1 receptor for angiotensin II, attenuates lipopolysaccharide-induced acute lung injury in Rat. Arch Biochem Biophys 481: 131–136PubMedCrossRefGoogle Scholar
  41. 41.
    Lipke AB, Matute-Bello G, Herrero R, Wong VA, Mongovin SM, Martin TR (2011) Death receptors mediate the adverse effects of febrile-range hyperthermia on the outcome of lipopolysaccharide-induced lung injury. Am J Physiol Lung Cell Mol Physiol 301: L60–70PubMedCrossRefGoogle Scholar
  42. 42.
    Lee WL, Slutsky AS (2010) Sepsis and endothelial permeability. N Engl J Med 363: 689–691PubMedCrossRefGoogle Scholar
  43. 43.
    Russell JA (2006) Management of sepsis. N Engl J Med 355: 1699–1713PubMedCrossRefGoogle Scholar
  44. 44.
    Raghavendran K, Pryhuber GS, Chess PR, Davidson BA, Knight PR, Notter RH (2008) Pharmacotherapy of acute lung injury and acute Respiratory distress syndrome. Curr Med Chem 15: 1911–1924PubMedCrossRefGoogle Scholar
  45. 45.
    Rice TW, Wheeler AP, Bernard GR, et al (2010) A Randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis. Crit Care Med 38: 1685–1694PubMedCrossRefGoogle Scholar
  46. 46.
    Vincent JL, Angus DC, Artigas A, et al (2003) Effects of drotrecogin alfa (activated) on organ dysfunction in the PROWESS trial. Crit Care Med 31: 834–840PubMedCrossRefGoogle Scholar
  47. 47.
    Matthay MA, Goolaerts A, Howard JP, Lee JW (2010) Mesenchymal stem cells for acute lung injury: preclinical evidence. Crit Care Med 38: S569–573PubMedCrossRefGoogle Scholar
  48. 48.
    Manzoni P, Rinaldi M, Cattani S, et al (2009) Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a Randomized trial. JAMA 302: 1421–1428PubMedCrossRefGoogle Scholar
  49. 49.
    Cruz DN, Antonelli M, Fumagalli R, et al (2009) Early use of polymyxin B hemoperfusion in abdominal septic shock: the EUPHAS Randomized controlled trial. JAMA 301: 2445–2452PubMedCrossRefGoogle Scholar
  50. 50.
    Cross AS, Opal SM (2003) A new paradigm for the treatment of sepsis: is it time to consider combination therapy? Ann Intern Med 138: 502–505PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • R. Herrero
  • I. Martin-Loeches
  • A. Artigas

There are no affiliations available

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