Molecular Medicine

, Volume 14, Issue 7–8, pp 465–475 | Cite as

Epithelial Cell Apoptosis and Neutrophil Recruitment in Acute Lung Injury—A Unifying Hypothesis? What We Have Learned from Small Interfering RNAs

  • Mario Perl
  • Joanne Lomas-Neira
  • Chun-Shiang Chung
  • Alfred Ayala
Review Article


In spite of protective ventilatory strategies, Acute Lung Injury (ALI) remains associated with high morbidity and mortality. One reason for the lack of therapeutic options might be that ALI is a co-morbid event associated with a diverse family of diseases and, thus, may be the result of distinct pathological processes. Among them, activated neutrophil- (PMN-) induced tissue injury and epithelial cell apoptosis mediated lung damage represent two potentially important candidate pathomechanisms that have been put forward. Several approaches have been undertaken to test these hypotheses, with substantial success in the treatment of experimental forms of ALI. With this in mind, we will summarize these two current hypotheses of ALI briefly, emphasizing the role of apoptosis in regulating PMN and/or lung epithelial cell responses. In addition, the contribution that Fas-mediated inflammation may play as a potential biological link between lung cell apoptosis and PMN recruitment will be considered, as well as the in vivo application of small interfering RNA (siRNA) as a novel approach to the inhibition of ALI and its therapeutic implications.



This work was supported in part by funds from the University of Ulm Medical School (M.P.) as well as NIH-RO1s GM53209 and HL73525 (A.A.).


  1. 1.
    Bernard GR et al. (1994) The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am. J. Respir. Crit. Care Med. 149:818–24.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Wheeler AP, Bernard GR. (2007) Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet. 369:1553–64.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Ashbaugh DG, Bigelow DB, Petty TL, Levine BE. (1967) Acute respiratory distress in adults. Lancet. 2:319–23.CrossRefGoogle Scholar
  4. 4.
    Brun-Buisson C et al. (2004) Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study. Intensive Care Med. 30:51–61.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Rubenfeld GD et al. (2005) Incidence and outcomes of acute lung injury. N Engl. J. Med. 353:1685–93.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Herridge MS, Angus DC. (2005) Acute lung injury—affecting many lives. N. Engl. J. Med. 353:1736–8.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Goss CH, Brower RG, Hudson LD, Rubenfeld GD. (2003) Incidence of acute lung injury in the United States. Crit. Care Med. 31:1607–11.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Yilmaz M et al. (2007) Six-month survival of patients with acute lung injury: prospective cohort study. Crit. Care Med. 35:2303–7.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Calfee CS et al. (2007) Trauma-associated lung injury differs clinically and biologically from acute lung injury due to other clinical disorders. Crit. Care Med. 35:2243–50.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Vincent JL, Zambon M. (2006) Why do patients who have acute lung injury/acute respiratory distress syndrome die from multiple organ dysfunction syndrome? Implications for management. Clin. Chest Med. 27:725–31.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Monchi M et al. (1998) Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am. J. Respir. Crit. Care Med. 158:1076–81.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Hopkins RO, Herridge MS. (2006) Quality of life, emotional abnormalities, and cognitive dysfunction in survivors of acute lung injury/acute respiratory distress syndrome. Clin. Chest Med. 27:679–89.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Herridge MS et al. (2003) One-year outcomes in survivors of the acute respiratory distress syndrome. N. Engl. J. Med. 348:683–93.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Suratt BT, Parsons PE. (2006) Mechanisms of acute lung injury/acute respiratory distress syndrome. Clin. Chest Med. 27:579–89.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    ARDS Network. (2000) 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. 342:1301–8.CrossRefGoogle Scholar
  16. 16.
    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. 155:1187–205.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Ware LB, Matthay MA. (2000) The acute respiratory distress syndrome. N. Engl. J. Med. 342:1334–49.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Burns AR, Smith CW, Walker DC. (2003) Unique structural features that influence neutrophil emigration into the lung. Physiol. Rev. 83:309–36.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Bachofen M, Weibel ER. (1982) Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin. Chest Med. 3:35–56.PubMedPubMedCentralGoogle Scholar
  20. 20.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Rinaldo JE, Borovetz H. (1985) Deterioration of oxygenation and abnormal lung microvascular permeability during resolution of leukopenia in patients with diffuse lung injury. Am. Rev. Respir. Dis. 131:579–83.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Azoulay E et al. (2002) Deterioration of previous acute lung injury during neutropenia recovery. Crit. Care Med. 30:781–6.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Steinberg KP et al. (1994) Evolution of broncho-alveolar cell populations in the adult respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 150(1):113–122.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Ayala A et al. (2002) Shock-induced neutrophil mediated priming for acute lung injury in mice: divergent effects of TLR-4 and TLR-4/FasL deficiency. Am. J. Pathol. 161:2283–94.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Lomas-Neira J, Chung CS, Perl M, Gregory S, Biffl W, Ayala A. (2006) Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge. Am. J. Physiol. Lung Cell. Mol. Physiol. 290:L51–8.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Stephens KE, Ishizaka A, Wu ZH, Larrick JW, Raffin TA. (1988) Granulocyte depletion prevents tumor necrosis factor-mediated acute lung injury in guinea pigs. Am. Rev. Respir. Dis. 138:1300–7.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Inoue S et al. (1995) Anti-neutrophil antibody attenuates the severity of acute lung injury in rats with experimental acute pancreatitis. Arch. Surg. 130:93–8.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Clark SC, Rao JN, Flecknell PA, Dark JH. (2003) Pentoxifylline is as effective as leukocyte depletion for modulating pulmonary reperfusion injury. J. Thorac. Cardiovasc. Surg. 126:2052–7.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Looney MR, Su X, Van Ziffle JA, Lowell CA, Matthay MA. (2006) Neutrophils and their Fc gamma receptors are essential in a mouse model of transfusion-related acute lung injury. J. Clin. Invest. 116:1615–23.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Heflin JAC, Brigham KL. (1981) Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J. Clin. Invest. 68:1253–60.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Till GO, Johnson KJ, Kunkel R, Ward PA. (1982) Intravascular activation of complement and acute lung injury. J. Clin. Invest. 69:1126–35.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Abraham E, Carmody A, Shenkar R, Arcaroli J. (2000) Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am. J. Physiol Lung Cell. Mol. Physiol. 279:L1137–45.PubMedCrossRefGoogle Scholar
  33. 33.
    Donnelly SC et al. (1993) Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups. Lancet. 341:643–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Pugin J, Ricou B, Steinberg KP, Suter PM, Martin TR. (1996) Proinflammatory activity in bron-choalveolar lavage fluids from patients with ARDS, a prominent role for interleukin-1. Am. J. Respir. Crit. Care Med. 153:1850–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Meduri GU et al. (1995) Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest. 108:1303–14.PubMedCrossRefGoogle Scholar
  36. 36.
    Siler TM, Swierkosz JE, Hyers TM, Fowler AA, Webster RO. (1989) Immunoreactive interleukin-1 in bronchoalveolar lavage fluid of high-risk patients and patients with the adult respiratory distress syndrome. Exp. Lung Res. 15:881–94.PubMedCrossRefGoogle Scholar
  37. 37.
    Meduri GU et al. (1995) Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time. Chest. 107:1062–73.PubMedCrossRefGoogle Scholar
  38. 38.
    Hammerschmidt DE, Weaver LJ, Hudson LD, Craddock PR, Jacob HS. (1980) Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Patho-physiological relevance and possible prognostic value. Lancet. 1:947–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Jacob HS, Craddock PR, Hammerschmidt DE, Moldow CF. (1980) Complement-induced granu-locyte aggregation: an unsuspected mechanism of disease. N. Engl. J. Med. 302:789–94.PubMedCrossRefGoogle Scholar
  40. 40.
    Zimmerman GA et al. (1999) Endothelial activation in ARDS. Chest. 116:18S–24S.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Park WY et al. (2001) Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 164:1896–903.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Schutte H et al. (1996) Bronchoalveolar and systemic cytokine profiles in patients with ARDS, severe pneumonia and cardiogenic pulmonary edema. Eur. Respir. J. 9:1858–67.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Suter PM et al. (1992) High bronchoalveolar levels of tumor necrosis factor and its inhibitors, in-terleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis. Am. Rev. Respir. Dis. 145:1016–22.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Goodman RB et al. (1996) Inflammatory cyto-kines in patients with persistence of the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 154:602–11.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Opal SM, Cross AS. (1999) Clinical trials for severe sepsis. Past failures, and future hopes. Infect. Dis. Clin. North Am. 13:285–97, vii.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Abraham E, Kaneko DJ, Shenkar R. (1999) Effects of endogenous and exogenous catecholamines on LPS-induced neutrophil trafficking and activation. Am. J. Physiol. 276:L1–8.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Shenkar R, Abraham E. (1999) Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein. J. Immunol. 163:954–62.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Parsey MV, Tuder RM, Abraham E. (1998) Neu- trophils are major contributors to intraparenchy-mal lung IL-1 beta expression after hemorrhage and endotoxemia. J. Immunol. 160:1007–13.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Miskolci V et al. (2007) NFkappaB is persistently activated in continuously stimulated human neu- trophils. Mol. Med. 13:134–42.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Yang KY, Arcaroli JJ, Abraham E. (2003) Early alterations in neutrophil activation are associated with outcome in acute lung injury. Am. J. Respir. Crit. Care Med. 167:1567–74.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Doerschuk CM. (2001) Mechanisms of leukocyte sequestration in inflamed lungs. Microcirculation. 8:71–88.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Skoutelis AT et al. (2000) Neutrophil deformabil- ity in patients with sepsis, septic shock, and adult respiratory distress syndrome. Crit. Care Med. 28:2355–9.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Doyle NA et al. (1997) Neutrophil margination, sequestration, and emigration in the lungs of L-selectin-deficient mice. J. Clin. Invest. 99:526–33.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Kubo H et al. (1999) L- and P-selectin and CD11/CD18 in intracapillary neutrophil sequestration in rabbit lungs. Am. J. Respir. Crit. Care Med. 159:267–74.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Simon SI et al. (1999) Signaling functions of L-se-lectin in neutrophils: alterations in the cytoskele-ton and colocalization with CD18. J. Immunol. 163:2891–901.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Doerschuk CM, Tasaka S, Wang Q. (2000) CD11/CD18-dependent and -independent neu-trophil emigration in the lungs: how do neu-trophils know which route to take? Am. J. Respir. Cell Mol. Biol. 23:133–6.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Williams MA, Solomkin JS. (1999) Integrin- mediated signaling in human neutrophil functioning. J. Leukoc. Biol. 65:725–36.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Lowell CA, Berton G. (1999) Integrin signal transduction in myeloid leukocytes. J. Leukoc. Biol. 65:313–20.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Schymeinsky J, Mocsai A, Walzog B. (2007) Neu-trophil activation via beta2 integrins (CD11/CD18): molecular mechanisms and clinical implications. Thromb. Haemost. 98:262–73.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Ley K. (2002) Integration of inflammatory signals by rolling neutrophils. Immunol. Rev. 186:8–18.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Nathan C et al. (1989) Cytokine-induced respiratory burst of human neutrophils: Dependence on extracellular matrix proteins and CD11/CD18 in- tegrins. J. Cell. Biol. 109:1341–9.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Walzog B et al. (1999) A role for beta(2) integrins (CD11/CD18) in the regulation of cytokine gene expression of polymorphonuclear neutrophils during the inflammatory response. FASEB J. 13:1855–65.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Perkins GD, Nathani N, McAuley DF, Gao F, Thickett DR. (2007) In vitro and in vivo effects of salbutamol on neutrophil function in acute lung injury. Thorax. 62:36–42.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Belperio JA et al. (2002) Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J. Clin. Invest. 110:1703–16.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Perl M et al. (2006) The pulmonary and hepatic immune microenvironment and its contribution to the early systemic inflammation following blunt chest trauma. Crit. Care Med. 34:1152–9.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Lomas-Neira JL, Chung CS, Grutkoski PS, Miller EJ, Ayala A. (2004) CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice. J. Leukoc. Biol. 76:58–64.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Lomas JL et al. (2003) Differential effects of macrophage inflammatory chemokine-2 and ker-atinocyte-derived chemokine on hemorrhage-induced neutrophil priming for lung inflammation: assessment by adoptive cells transfer in mice. Shock. 19:358–65.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Martin TR. (2002) Neutrophils and lung injury: getting it right. J. Clin. Invest. 110:1603–5.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Shasby DM et al. (1982) Granulocytes mediate acute edematous lung injury in rabbits and in isolated rabbit lungs perfused with phorbol myristate acetate: role of oxygen radicals. Am. Rev. Respir. Dis. 125:443–7.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Wang W, Suzuki Y, Tanigaki T, Rank DR, Raffin TA. (1994) Effect of the NADPH oxidase inhibitor apocynin on septic lung injury in guinea pigs. Am. J. Respir. Crit. Care Med. 150:1449–52.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Kubo H et al. (1996) Preservation of complement-induced lung injury in mice with deficiency of NADPH oxidase. J. Clin. Invest. 97:2680–4.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Kristof AS, Goldberg P, Laubach V, Hussain SN. (1998) Role of inducible nitric oxide synthase in endotoxin-induced acute lung injury. Am. J. Respir. Crit. Care Med. 158:1883–9.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Fialkow L, Wang Y, Downey GP. (2007) Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic. Biol. Med. 42:153–64.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Endo S et al. (2006) Sivelestat sodium hydrate improves septic acute lung injury by reducing alveolar dysfunction. Res. Commun. Mol. Pathol. Pharmacol. 119:53–65.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Belaaouaj A et al. (1998) Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat. Med. 4:615–8.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Tkalcevic J et al. (2000) Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity. 12:201–10.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Delclaux C et al. (1997) Gelatinases in epithelial lining fluid of patients with adult respiratory distress syndrome. Am. J. Physiol. 272:L442–51.PubMedPubMedCentralGoogle Scholar
  78. 78.
    Carney DE et al. (1999) Matrix metalloproteinase inhibitor prevents acute lung injury after cardiopulmonary bypass. Circulation. 100:400–6.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Kawabata K, Hagio T, Matsuoka S. (2002) The role of neutrophil elastase in acute lung injury. Eur. J. Pharmacol. 451:1–10.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Moraes TJ, Zurawska JH, Downey GP. (2006) Neutrophil granule contents in the pathogenesis of lung injury. Curr. Opin. Hematol 13:21–7.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Dunican AL, Leuenroth SJ, Grutkoski P, Ayala A, Simms HH. (2000) TNFalpha-induced suppression of PMN apoptosis is mediated through interleukin-8 production. Shock. 14:284–8.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Dunican AL, Leuenroth SJ, Ayala A, Simms HH. (2000) CXC chemokine suppression of polymor-phonuclear leukocytes apoptosis and preservation of function is oxidative stress independent. Shock. 13:244–50.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Jimenez MF et al. (1997) Dysregulated expression of neutrophil apoptosis in the systemic inflammatory response syndrome. Arch. Surg. 132:1263–9.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Ertel W et al. (1999) Granulocyte colony-stimulating factor inhibits neutrophil apoptosis at the local site after severe head and thoracic injury. J. Trauma. 46:784–92.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Biffl WL et al. (1999) Neutrophils are primed for cytotoxicity and resist apoptosis in injured patients at risk for multiple organ failure. Surgery. 126:198–202.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Biffl WL et al. (2001) Neutrophil apoptosis is delayed by trauma patients’ plasma via a mechanism involving proinflammatory phospholipids and protein kinase C. Surg. Infect. (Larchmt). 2:289–93.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Chitnis D, Dickerson C, Munster AM, Winchurch RA. (1996) Inhibition of apoptosis in polymor-phonuclear neutrophils from burn patients. J. Leukoc. Biol. 59:835–9.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Taneja R et al. (2004) Delayed neutrophil apoptosis in sepsis is associated with maintenance of mitochondrial transmembrane potential and reduced caspase-9 activity. Crit. Care Med. 32:1460–9.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Fialkow L et al. (2006) Neutrophil apoptosis: a marker of disease severity in sepsis and sepsis-induced acute respiratory distress syndrome. Crit. Care. 10:R155.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Goodman ER et al. (1999) Role of granulocyte-macrophage colony-stimulating factor and its receptor in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis. Arch. Surg. 134:1049–54.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Dunican A, Grutkoski P, Leuenroth S, Ayala A, Simms HH. (2000) Neutrophils regulate their own apoptosis via preservation of CXC receptors. JSurg. Res. 90:32–8.CrossRefGoogle Scholar
  92. 92.
    Abraham E. (2003) Neutrophils and acute lung injury. Crit. Care Med. 31:S195–9.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Nelson S et al. (1998) A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group. J. Infect. Dis. 178:1075–80.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Matute-Bello G et al. (2000) Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit. Care Med. 28:1–7.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Lagasse E, Weissman IL. (1994) bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages. J. Exp. Med. 179:1047–52.CrossRefGoogle Scholar
  96. 96.
    Perl M et al. (2007) Beneficial versus detrimental effects of neutrophils are determined by the nature of the insult. J. Am. Coll. Surg. 204:840–52.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Teder P et al. (2002) Resolution of lung inflammation by CD44. Science. 296:155–8.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Laufe MD, Simon RH, Flint A, Keller JB. (1986) Adult respiratory distress syndrome in neutropenic patients. Am. J. Med. 80:1022–6.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Vansteenkiste JF, Boogaerts MA. (1989) Adult respiratory distress syndrome in neutropenic leukemia patients. Blut. 58:287–90.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Ognibene FP et al. (1986) Adult respiratory distress syndrome in patients with severe neutropenia. N. Engl. J. Med. 315:547–51.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Wunderink R et al. (2001) Filgrastim in patients with pneumonia and severe sepsis or septic shock. Chest. 119:523–9.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    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. 88:864–75.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Walker DC, Behzad AR, Chu F. (1995) Neutrophil migration through preexisting holes in the basal laminae of alveolar capillaries and epithelium during streptococcal pneumonia. Microvasc. Res. 50:397–416.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Ware LB, Matthay MA. (2001) Alveolar fluid clearance is impaired in the majority of patients with acute lung injury and the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 163:1376–83.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Modelska K, Pittet JF, Folkesson HG, Courtney Broaddus V, Matthay MA. (1999) Acid-induced lung injury. Protective effect of anti-interleukin-8 pretreatment on alveolar epithelial barrier function in rabbits. Am. J. Respir. Crit. Care Med. 160:1450–6.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Sznajder JI. (1999) Strategies to increase alveolar epithelial fluid removal in the injured lung. Am. J. Respir. Crit. Care Med. 160:1441–2.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Martin TR, Hagimoto N, Nakamura M, Matute-Bello G. (2005) Apoptosis and epithelial injury in the lungs. Proc. Am. Thorac. Soc. 2:214–20.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Martin TR, Nakamura M, Matute-Bello G. (2003) The role of apoptosis in acute lung injury. Crit. Care Med. 31:S184–8.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Matthay MA, Wiener-Kronish JP. (1990) Intact epithelial barrier function is critical for the resolution of alveolar edema in humans. Am. Rev. Respir. Dis. 142:1250–7.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Strohmaier W et al. (2005) Bilateral lavage with diluted surfactant improves lung function after unilateral lung contusion in pigs. Crit. Care Med. 33:2286–93.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Greene KE et al. (1999) Serial changes in surfactant-associated proteins in lung and serum before and after onset of ARDS. Am. J. Respir. Crit. Care Med. 160:1843–50.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Bardales RH, Xie SS, Schaefer RF, Hsu SM. (1996) Apoptosis is a major pathway responsible for the resolution of type II pneumocytes in acute lung injury. Am. J. Pathol. 149:845–52.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Guinee D Jr et al. (1997) The potential role of BAX and BCL-2 expression in diffuse alveolar damage. Am. J. Pathol. 151:999–1007.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Bem RA, Bos AP, Matute-Bello G, van TM, van Woensel JB. (2007) Lung epithelial cell apoptosis during acute lung injury in infancy. Pediatr. Crit. Care Med. 8:132–7.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Matute-Bello G et al. (1997) Neutrophil apoptosis in the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 156:1969–77.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Matute-Bello G et al. (1999) Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS). J. Immunol. 163:2217–25.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Miyake Y et al. (2007) Protective role of macrophages in noninflammatory lung injury caused by selective ablation of alveolar epithelial type II Cells. J. Immunol. 178:5001–9.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Kawasaki M et al. (2000) Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor. Am. J. Pathol. 157:597–603.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Chen H et al. (2007) Anti-apoptotic PTD-FNK protein suppresses lipopolysaccharide-induced acute lung injury in rats. Exp. Mol. Pathol. 83:377–84.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Kitamura Y et al. (2001) Fas/FasL-dependent apoptosis of alveolar cells after lipopolysaccharide-induced lung injury in mice. Am. J. Respir. Crit. Care Med. 163:762–9.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Nakamura M et al. (2004) Differential response of human lung epithelial cells to Fas-induced apoptosis. Am. J. Pathol. 164:1949–58.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Lee KS et al. (2007) Evaluation of bronchoalveolar lavage fluid from ARDS patients with regard to apoptosis. Respir. Med. 102:464–9.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Albertine KH 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. 161:1783–96.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Hashimoto S et al. (2000) Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 161:237–43.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Kiener PA et al. (1997) Human monocytic cells contain high levels of intracellular Fas ligand: rapid release following cellular activation. J. Immunol. 159:1594–8.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Serrao KL, Fortenberry JD, Owens ML, Harris FL, Brown LA. (2001) Neutrophils induce apoptosis of lung epithelial cells via release of soluble Fas ligand. Am. J. Physiol. Lung Cell. Mol. Physiol. 280:L298–305.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Powell WC, Fingleton B, Wilson CL, Boothby M, Matrisian LM. (1999) The metalloproteinase matrilysin proteolytically generates active soluble Fas ligand and potentiates epithelial cell apoptosis. Curr. Biol. 9:1441–7.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Matsuno H et al. (2001) Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand. J. Rheumatol. 28:22–8.PubMedPubMedCentralGoogle Scholar
  129. 129.
    Cheng J et al. (1994) Protection from Fas-mediated apoptosis by a soluble form of the Fas molecule. Science. 263:1759–62.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Matute-Bello G et al. (2001) Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation. Am. J. Pathol. 158:153–61.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Matute-Bello G et al. (2005) Fas-mediated acute lung injury requires fas expression on non-myeloid cells of the lung. J. Immunol. 175:4069–75.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Perl M et al. (2007) Fas-induced pulmonary apoptosis and inflammation during indirect acute lung injury. Am. J. Respir. Crit. Care Med. 176:591–601.CrossRefGoogle Scholar
  133. 133.
    Matute-Bello G et al. (2001) Fas/Fas ligand system mediates epithelial injury, but not pulmonary host defenses, in response to inhaled bacteria. Infect. Immun. 69:5768–76.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Tateda K et al. (2003) Hyperoxia mediates acute lung injury and increased lethality in murine Legionella pneumonia: the role of apoptosis. J. Immunol. 170:4209–16.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Grassme H et al. (2000) CD95/CD95 ligand interactions on epithelial cells in host defense to Pseudomonas aeruginosa. Science. 290:527–30.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Liu AN et al. (1999) Perforin-independent CD8(+) T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha: relative insensitivity to Fas ligand. Am. J. Respir. Cell Mol. Biol. 20:849–58.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Buccellato LJ, Tso M, Akinci OI, Chandel NS, Budinger GR. (2004) Reactive oxygen species are required for hyperoxia-induced Bax activation and cell death in alveolar epithelial cells. J. Biol. Chem. 279:6753–60.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Arai H, Gordon D, Nabel EG, Nabel GJ. (1997) Gene transfer of Fas ligand induces tumor regression in vivo. Proc. Natl. Acad. Sci. U. S. A. 94:13862–7.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Wortinger MA et al. (2003) Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue. Immunology. 110:225–33.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Matute-Bello G, Winn RK, Martin TR, Liles WC. (2004) Sustained lipopolysaccharide-induced lung inflammation in mice is attenuated by functional deficiency of the Fas/Fas ligand system. Clin. Diagn. Lab. Immunol. 11:358–61.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Neff TA et al. (2005) Relationship of acute lung inflammatory injury to Fas/FasL system. Am. J. Pathol. 166:685–94.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Hohlbaum AM, Gregory MS, Ju ST, Marshak Rothstein A. (2001) Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors. J. Immunol. 167:6217–24.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Park DR et al. (2003) Fas (CD95) induces pro-inflammatory cytokine responses by human monocytes and monocyte-derived macrophages. J. Immunol. 170:6209–16.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Yamaoka-Tojo M et al. (2003) Dual response to Fas ligation in human endothelial cells: apoptosis and induction of chemokines, interleukin-8 and monocyte chemoattractant protein-1. Coron. Artery Dis. 14:89–94.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Guo Z, Zhang M, Tang H, Cao X. (2005) Fas signal links innate and adaptive immunity by promoting dendritic-cell secretion of CC and CXC chemokines. Blood. 106:2033–41.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Guo Z et al. (2003) Fas ligation induces IL-1beta-dependent maturation and IL-1beta-independent survival of dendritic cells: different roles of ERK and NF-kappaB signaling pathways. Blood. 102:4441–7.PubMedCrossRefPubMedCentralGoogle Scholar
  147. 147.
    Rescigno M et al. (2000) Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J. Exp. Med. 192:1661–8.PubMedCrossRefPubMedCentralGoogle Scholar
  148. 148.
    Choi C et al. (2001) Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. Cancer Res. 61:3084–91.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Choi C, Gillespie GY, Van Wagoner NJ, Benveniste EN. (2002) Fas engagement increases expression of interleukin-6 in human glioma cells. J. Neurooncol. 56:13–9.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Schaub FJ et al. (2000) Fas/FADD-mediated activation of a specific program of inflammatory gene expression in vascular smooth muscle cells. Nat. Med. 6:790–6.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Hagimoto N et al. (1999) Induction of interleukin-8 secretion and apoptosis in bronchiolar epithelial cells by Fas ligation. Am. J. Respir. Cell Mol. Biol. 21:436–45.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Perl M et al. (2005) Silencing of fas, but not cas-pase-8, in lung epithelial cells ameliorates pulmonary apoptosis, inflammation, and neutrophil influx after hemorrhagic shock and sepsis. Am. J. Pathol. 167:1545–59.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Kumar LD, Clarke AR. (2007) Gene manipulation through the use of small interfering RNA (siRNA): from in vitro to in vivo applications. Adv. Drug Deliv. Rev. 59:87–100.PubMedCrossRefGoogle Scholar
  154. 154.
    Aigner A. (2007) Nonviral in vivo delivery of therapeutic small interfering RNAs. Curr. Opin. Mol. Ther. 9:345–52.PubMedGoogle Scholar
  155. 155.
    de FA, Vornlocher HP, Maraganore J, Lieberman J. (2007) Interfering with disease: a progress report on siRNA-based therapeutics. Nat. Rev. Drug Discov. 6:443–53.CrossRefGoogle Scholar
  156. 156.
    Martin SE, Caplen NJ. (2007) Applications of RNA interference in mammalian systems. Annu. Rev. Genomics Hum. Genet. 8:81–108.PubMedCrossRefGoogle Scholar
  157. 157.
    Ernst N et al. (1999) Interaction of liposomal and polycationic transfection complexes with pulmonary surfactant. J. Gene Med. 1:331–40.PubMedCrossRefGoogle Scholar
  158. 158.
    Thomas M et al. (2005) Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung. Proc. Natl. Acad. Sci. U. S. A. 102: 5679–84.PubMedCrossRefPubMedCentralGoogle Scholar
  159. 159.
    Thomas M, Lu JJ, Chen J, Klibanov AM. (2007) Non-viral siRNA delivery to the lung. Adv. Drug Deliv. Rev. 59:124–33.PubMedCrossRefGoogle Scholar
  160. 160.
    Li BJ et al. (2005) Using siRNA in prophylactic and therapeutic regimens against SARS coronavirus in Rhesus macaque. Nat. Med. 11:944–51.PubMedCrossRefGoogle Scholar
  161. 161.
    Massaro D, Massaro GD, Clerch LB. (2004) Noninvasive delivery of small inhibitory RNA and other reagents to pulmonary alveoli in mice. Am. J. Physiol. Lung Cell. Mol. Physiol. 287(5):L1066–L1070.PubMedCrossRefGoogle Scholar
  162. 162.
    Zhang X et al. (2004) Small interfering RNA targeting heme oxygenase-1 enhances ischemia-reperfusion-induced lung apoptosis. J. Biol. Chem. 279:10677–84.PubMedCrossRefGoogle Scholar
  163. 163.
    Akhtar S, Benter IF. (2007) Nonviral delivery of synthetic siRNAs in vivo. J. Clin. Invest. 117:3623–32.PubMedCrossRefGoogle Scholar
  164. 164.
    Lomas-Neira JL, Chung CS, Wesche DE, Perl M, Ayala A. (2005) In vivo gene silencing (with siRNA) of pulmonary expression of MIP-2 versus KC results in divergent effects on hemorrhage-induced, neutrophil-mediated septic acute lung injury. J. Leukoc. Biol. 77:846–53.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR. (2003) Activation of the interferon system by short-interfering RNAs. Nat. Cell Biol. 5:834–9.PubMedCrossRefPubMedCentralGoogle Scholar
  166. 166.
    Moss EG, Taylor JM. (2003) Small-interfering RNAs in the radar of the interferon system. Nat. Cell Biol. 5:771–2.PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. (2001) Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 413:732–8.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Hornung V et al. (2005) Sequence-specific potent induction of IFN-alpha by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med. 11:263–70.PubMedCrossRefGoogle Scholar
  169. 169.
    Robbins MA, Rossi JJ. (2005) Sensing the danger in RNA. Nat. Med. 11:250–1.PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Heidel JD, Hu S, Liu XF, Triche TJ, Davis ME. (2004) Lack of interferon response in animals to naked siRNAs. Nat. Biotechnol. 22:1579–82.PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Akira S. (2003) Toll-like receptor signaling. J. Biol. Chem. 278:38105–8.PubMedCrossRefGoogle Scholar
  172. 172.
    Wang XM, Kim HP, Song R, Choi AM. (2006) Caveolin-1 confers antiinflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. Am. J. Respir. Cell Mol. Biol. 34:434–42.PubMedCrossRefGoogle Scholar
  173. 173.
    Ulanova M et al. (2007) Involvement of Syk protein tyrosine kinase in LPS-induced responses in macrophages. J. Endotoxin Res. 13:117–25.PubMedCrossRefGoogle Scholar
  174. 174.
    Tephly LA, Carter AB. (2007) Constitutive NADPH oxidase and increased mitochondrial respiratory chain activity regulate chemokine gene expression. Am. J. Physiol. Lung Cell. Mol. Physiol. 293:L1143–55.PubMedCrossRefGoogle Scholar
  175. 175.
    Perl M, Chung CS, Ayala A. (2005) Apoptosis. Crit. Care Med. 33:S526–9.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Mario Perl
    • 1
  • Joanne Lomas-Neira
    • 2
  • Chun-Shiang Chung
    • 2
  • Alfred Ayala
    • 2
  1. 1.Department of Traumatology, Hand- and Reconstructive SurgeryUniversity of Ulm Medical SchoolUlmGermany
  2. 2.Division of Surgical Research, Department of SurgeryRhode Island Hospital and Brown UniversityProvidenceUSA

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