Pro- and Anti-inflammatory Cytokines and Apoptosis in Acute Lung Injury

  • S. Uhlig
  • D. Burdon
Conference paper


Sepsis is the most frequent cause for the development of acute lung injury (ALI). Acute lung injury is a complex disease that so far has defied mechanistic definitions. However, it is widely accepted that pro-inflammatory mediators and overshooting immune reactions shape the course of the disease. Recently, it has been suggested that apoptosis might play an important role in the pathogenesis of ALI. This has posed the question of how pro- (e.g., TNF, IFN-γ, IL-1) and anti-inflammatory (e.g., IL-10, TGFβ, PGE2) mediators affect apoptosis in the lung. The beneficial properties of apoptosis during pulmonary development and in the resolution of inflammation are well recognized. However, bacterial endotoxins (lipopolysaccharide, LPS) and infections elicit apoptosis in cells of the lung [2]. An important question therefore is whether pulmonary apoptosis is detrimental under these conditions. It is the scope of the present manuscript to review the current knowledge on the effects of pro- and anti-inflammatory factors and cytokines on apoptosis in the lung and its possible consequences for the development of ALI. We will not address intracellular signalling mechanisms of apoptosis, a topic for which several excellent reviews are available [5–7]. We will rather focus on pathophysiological implications of apoptosis in the lungs in the context of ALI. After a brief look at apoptosis, we will describe the effect of cytokines on apoptosis in individual cell populations in the lung, before discussing the consequences for the whole organ.


Acute Lung Injury Pulmonary Fibrosis Acute Respiratory Distress Syndrome Respir Crit Alveolar Epithelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Nicholson DW (2000) From bench to clinic with apoptosis-based therapeutic agents. Nature 407: 810–816PubMedCrossRefGoogle Scholar
  2. 2.
    Bohlinger I, Leist M, Gantner F, et al (1996) DNA fragmentation in mouse organs during endotoxic shock. Am J Pathol 149: 1381–1393PubMedGoogle Scholar
  3. 3.
    Hiramatsu M, Hotchkiss RS, Karl IE, Buchman TG (1997) Cecal ligation and puncture (CLP) induces apoptosis in thymus, spleen, lung, and gut by an endotoxin and TNF-independent pathway. Shock 7: 247–253PubMedCrossRefGoogle Scholar
  4. 4.
    Vernooy JH, Dentener MA, van Suylen RI, et al (2001) Intratracheal instillation of lipopolysaccharide in mice induces apoptosis in bronchial epithelial cells: no role for tumor necrosis factor-alpha and infiltrating neutrophils. Am J Respir Cell Mol Bio 24: 569–576Google Scholar
  5. 5.
    Leist M, Jäättela M (2001) Four deaths and funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2: 1–10CrossRefGoogle Scholar
  6. 6.
    Krammer PH (2000) CD95’s deadly mission in the immune system. Nature 407: 789–795PubMedCrossRefGoogle Scholar
  7. 7.
    Kuwano K, Hara N (2000) Signal transduction pathways of apoptosis and inflammation induced by the tumor necrosis factor receptor family. Am J Respir Cell Mol Biol 22: 147–149PubMedGoogle Scholar
  8. 8.
    Leist M, Gantner F, Bohlinger I, et al (1995) Tumor necrosis factor-induced hepatocyte apoptosis precedes liver failure in experimental murine shock models. Am J Pathol 146: 1220–1234PubMedGoogle Scholar
  9. 9.
    Künstle G, Leist M, Uhlig S, et al (1997) ICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by TNF-alpha. Immunol Lett 55: 5–10PubMedCrossRefGoogle Scholar
  10. 10.
    Leist M, Single B, Castoldi AF, et al (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185: 1481–1486PubMedCrossRefGoogle Scholar
  11. 11.
    Weisser M, Tiegs G, Wendel A, Uhlig S (1998) Quantification of apoptotic and lytic cell death by video microscopy in combination with artificial neural networks. Cytometry 31: 20–28PubMedCrossRefGoogle Scholar
  12. 12.
    Screaton G, Xu X-N (2000) T cell life and death signalling via TNF receptor family members. Curr Opin Immunol 12: 316–322PubMedCrossRefGoogle Scholar
  13. 13.
    Tannahill CL, Fukuzuka K, Marum T, et al (1999) Discordant tumor necrosis factor-alpha superfamily gene expression in bacterial peritonitis and endotoxemic shock. Surgery 126: 349–357PubMedCrossRefGoogle Scholar
  14. 14.
    Kawasaki M, Kuwano K, Hagimoto N, et al (2000) Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor. Am J Pathol 157: 597–603PubMedCrossRefGoogle Scholar
  15. 15.
    Kuwano K, Kunitake R, Maeyama T, et al (2001) Attenuation of bleomycin-induced pneumopathy in mice by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 280: L316–L325PubMedGoogle Scholar
  16. 16.
    Hoyt DG, Mannix RJ, Rusnak JM, et al (1995) Collagen is a survival factor against LPS-induced apoptosis in cultured sheep pulmonary artery endothelial cells. Am J Physiol 269: L171–L177PubMedGoogle Scholar
  17. 17.
    Maeda K, Abello PA, Abraham MR, et al (1995) Endotoxin induces organ-specific endothelial cell injury. Shock 3: 46–50PubMedGoogle Scholar
  18. 18.
    Hoyt DG, Mannix RJ, Gerritsen ME, et al (1996) Integrins inhibit LPS-induced DNA strand breakage in cultured lung endothelial cells. Am J Physiol 270: L689–L694PubMedGoogle Scholar
  19. 19.
    Fujita M, Kuwano K, Kunitake R, et al (1998) Endothelial cell apoptosis in lipopolysaccharideinduced lung injury in mice. Int Arch Allergy Immunol 117: 202–208PubMedCrossRefGoogle Scholar
  20. 20.
    Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S. et al (1997) Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation. J Exp Med 186: 1831–1841PubMedCrossRefGoogle Scholar
  21. 21.
    Polunovsky VA, Wendt CH, Ingbar DH, et al (1994) Induction of endothelial cell apoptosis by TNFa: Modulation by inhibitors of protein synthesis. Exp Cell Res 214: 584–594PubMedCrossRefGoogle Scholar
  22. 22.
    Petrache I, Verin AD, Crow MT, et al (2001) Differential effect of MLC kinase in TNF-alphainduced endothelial cell apoptosis and barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 280: L1168–L1178PubMedGoogle Scholar
  23. 23.
    Seydel U, Ulmer AJ, Uhlig S, Rietschel ET (2000) Lipopolysaccharide, a membrane-forming and inflammation-inducing bacterial macromolecule. In: Zimmer G (ed) Membrane Structure in Disease and Drug Therapy. Marcel Dekker Inc., New York, pp 217–252.Google Scholar
  24. 24.
    Falk S, Göggel R, Heydasch U, et al (1999) Quinolines attenuate PAF-induced pulmonary pressor responses and edema formation. Am J Respir Crit Care Med 160: 1734–1742PubMedGoogle Scholar
  25. 25.
    Gatti S, Faggioni R, Echtenacher B, Ghezzi P (1993) Role of tumour necrosis factor and reactive oxygen intermediates in lipopolysaccharide-induced pulmonary oedema and lethality. Clin Exp Immunol 91: 456–461PubMedCrossRefGoogle Scholar
  26. 26.
    Mizgerd JP, Peschon JJ, Doerschuk CM (2000) Roles of tumor necrosis factor receptor signaling during murine Eschericia Coli pneumonia. Am J Respir Cell Mol Biol 22: 85–91PubMedGoogle Scholar
  27. 27.
    Nelson S, Bagby GJ, Bainton BG, et al (1989) Compartimentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response. J Infect Dis 159: 189–194PubMedCrossRefGoogle Scholar
  28. 28.
    Dehoux MS, Boutten A, Ostinelli J, et al (1994) Compartimentalized cytokine production within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 150: 710–716PubMedGoogle Scholar
  29. 29.
    Haitsma JJ, Uhlig S, Göggel R et al (2000) Ventilator-induced lung injury leads to loss of alveolar and systemic compartmentalization of TNF-a. Intens Care Med 26: 1515–1522CrossRefGoogle Scholar
  30. 30.
    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: 762–769PubMedGoogle Scholar
  31. 31.
    Matute-Bello G, Winn RK, Jonas M, et al (2001) Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation. Am J Pathol 158: 153–161PubMedCrossRefGoogle Scholar
  32. 32.
    Tesfaigzi J, Wood MB, Johnson NF, Nikula KJ (1998) Apoptosis is a pathway responsible for the resolution of endotoxin-induced alveolar type II cell hyperplasia in the rat. Int J Exp Pathol 79: 303–311PubMedCrossRefGoogle Scholar
  33. 33.
    Fehrenbach H, Kasper M, Tschernig T, et al (1999) Keratinocyte growth factor-induced hyperplasia of rat alveolar type H cells in vivo is resolved by differentiation into type I cells and by apoptosis. Eur Respir J 14: 534–544PubMedCrossRefGoogle Scholar
  34. 34.
    Fehrenbach H, Kasper M, Koslowski R, et al (2000) Alveolar epithelial type II cell apoptosis in vivo during resolution of keratinocyte growth factor-induced hyperplasia in the rat. Histochem Cell Biol 114: 49–61PubMedGoogle Scholar
  35. 35.
    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: 845–852PubMedGoogle Scholar
  36. 36.
    Mallampalli RK, Peterson EJ, Brent Carter A, et al (1999) TNF-a increases ceramide without inducing apoptosis in alveolar type II epithelial cells. Am J Respir Cell Mol Biol 20: L481–L490Google Scholar
  37. 37.
    Kampf C, Relova AJ, Sandler S, Roomans GM (1999) Effects of TNF-a IFN-g and IL-lb on normal human bronchial epithelial cells. Eur Respir J 14: 84–91PubMedCrossRefGoogle Scholar
  38. 38.
    Trifilieff A, Futjitani Y, Coyle AJ, Bertrand C (1999) Fas-induced death of a murine pulmonary epithelial cell line: modulation by inflammatory cytokines. Fundam Clin Pharmacol 13: 656–661PubMedCrossRefGoogle Scholar
  39. 39.
    Liu AN, Mohammed AZ, Rice WR, 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: 849–858PubMedGoogle Scholar
  40. 40.
    Wang R, Alam G, Zagariya A, et al (2000) Apoptosis of lung epithelial cells in response to TNF-alpha requires angiotensin II generation de novo. J Cell Physiol 185: 253–259PubMedCrossRefGoogle Scholar
  41. 41.
    Boudreau N, Sympson CJ, Werb Z, Bissell MJ (1995) Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267: 891–893PubMedCrossRefGoogle Scholar
  42. 42.
    Boudreau N, Werb Z, Bissell MJ (1996) Suppression of apoptosis by basement membrane requires three-dimensional tissue organization and withdrawal from the cell cycle. Proc Natl Acad Sci U S A 93: 3509–3513PubMedCrossRefGoogle Scholar
  43. 43.
    Wen LP, Madani K, Fahrni JA, et al (1997) Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN-gamma and Fas. Am J Physiol 273: L921–L929PubMedGoogle Scholar
  44. 44.
    Thompson EB (1999) Mechanisms of T-cell apoptosis induced by glucocorticoids. Trends Endocrin Metabolism 10: 353–358CrossRefGoogle Scholar
  45. 45.
    Fine A, Andersonm NL, Rothstein TL, et al (1997) Fas expression in pulmonary alveolar type II cells. Am J Physiol 273: L64–L71PubMedGoogle Scholar
  46. 46.
    Gochuico BR, Williams MC, Fine A (1997) Simultaneous in situ hybridization and TUNEL to identify cells undergoing apoptosis. Histochem J 29: 413–418PubMedCrossRefGoogle Scholar
  47. 47.
    Matute-Bello G, Liles WC, Frevert CW, et al (2001) Recombinant human Fas ligand induces alveolar epithelial cell apoptosis and lung injury in rabbits. Am J Physiol Lung Cell Mol Physiol 281: L328–L335PubMedGoogle Scholar
  48. 48.
    Zhang J, Wenthold RJ, Yu ZX, et al (1995) Characterization of the pulmonary lesions induced in rats by human recombinant interleukin-2. Toxicol Pathol 23: 653–666PubMedCrossRefGoogle Scholar
  49. 49.
    Rensing-Ehl A, Hess S, Ziegler-Heitbrock HW, et al (1995) Fas/Apo-1 activates nuclear factor kappa B and induces interleukin-6 production. J Inflamm 45: 161–174PubMedGoogle Scholar
  50. 50.
    Ponton A, Clement MV, Stamenkovic I (1996) The CD95 (APO-l/Fas) receptor activates NF-kappaB independently of its cytotoxic function. J Biol Chem 271: 8991–8995PubMedCrossRefGoogle Scholar
  51. 51.
    Miwa K, Asano M, Horai R, et al (1998) Caspase 1-independent IL- lbeta release and inflammation induced by the apoptosis inducer Fas ligand. Nat Med 4: 1287–1292PubMedCrossRefGoogle Scholar
  52. 52.
    Chen JJ, Sun Y, Nabel GJ (1998) Regulation of the proinflammatory effects of Fas ligand (CD95L). Science 282: 1714–1717PubMedCrossRefGoogle Scholar
  53. 53.
    Filippatos G, Tilak M, Piniloss H, Uhal BD (2001) Regulation of apoptosis by angiotensin II in the heart and lungs. Int J Mol Med 7: 273–280PubMedGoogle Scholar
  54. 54.
    Wang R, Ramos C, Joshi I, et al (1999) Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides. Am J Physiol 277: L1158–L1164PubMedGoogle Scholar
  55. 55.
    Wang R, Zagariya A, Ang E, et al (1999) Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction. Am J Physiol 277: L1245–L1250PubMedGoogle Scholar
  56. 56.
    Wang R, Ibarra-Sunga O, Verlinski L, et al (2000) Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. Am J Physiol Lung Cell Mol Physiol 279: L143–L151PubMedGoogle Scholar
  57. 57.
    Edwards YS, Sutherland LM, Murray AW (2000) NO protects alveolar type II cells from stretch-induced apoptosis. A novel role for macrophages in the lung. Am J Physiol Lung Cell Mol Physiol 279: L1236–L1242PubMedGoogle Scholar
  58. 58.
    Yamamoto T, Ebe Y, Hasegawa G, et al (1999) Expression of scavenger receptor class A and CD14 in lipopolysaccharide-induced lung injury. Pathol Intern 49: 983–992CrossRefGoogle Scholar
  59. 59.
    Savill J, Fadok V (2000) Corpse clearance defines the meaning of cell death. Nature 407: 784–788PubMedCrossRefGoogle Scholar
  60. 60.
    Henson PM, Bratton DL, Fadok VA (2001) The phosphatidylserine receptor: a crucial molecular switch? Nat Rev Mol Cell Biol 2: 627–633PubMedCrossRefGoogle Scholar
  61. 61.
    Fadok VA, Bratton DL, Guthrie L, Henson PM (2001) Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J Immunol 166: 6847–6854PubMedGoogle Scholar
  62. 62.
    Liu Y, Cousin JM, Hughes J, et al (1999) Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J Immunol 162: 3639–3646PubMedGoogle Scholar
  63. 63.
    Giles KM, Ross K, Rossi AG (2001) Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation, and high levels of active rac. J Immunol 167: 976–986PubMedGoogle Scholar
  64. 64.
    Bingisser R, Stey C, Weller M, et al (1996) Apoptosis in human alveolar macrophages is induced by endotoxin and is modulated by cytokines. Am J Respir Cell Mol Biol 15: 64–70PubMedGoogle Scholar
  65. 65.
    Herlihy JP, Vermeulen MW, Hales CA (1996) Human alveolar macrophages prevent apoptosis in polymorphonuclear leukocytes. Am J Physiol 271: L681–L687PubMedGoogle Scholar
  66. 66.
    Wedmore CV, Williams TJ (1981) Control of vascular permeability by polymorphonuclear leukocytes in inflammation. Nature 289: 646–650PubMedCrossRefGoogle Scholar
  67. 67.
    Doherty DE, Downey GP, Worthen GS, et al (1988) Monocyte retention and migration in pulmonary inflammation. Requirement for neutrophils. Lab Invest 59: 200–213PubMedGoogle Scholar
  68. 68.
    Spitznagel JK (1990) Antibiotic proteins of human neutrophils. J Clin Invest 86: 1381–1386PubMedCrossRefGoogle Scholar
  69. 69.
    Haslett C, Jose PJ, Giclas PC et al (1989) Cessation of neutrophil influx in C5a-induced acute experimental arthritis is associated with loss of chemoattractant activity from the joint space. J Immunol 142: 3510–3517PubMedGoogle Scholar
  70. 70.
    Hurley JV (1983) Termination of acute inflammation: 1. Resolution. In: Hurley JV (ed) Acute inflammation 2nd edn, Churchill Livingston, London.Google Scholar
  71. 71.
    Savill JS, Wyllie AH, Henson JE, et al (1989) Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J Clin Invest 83: 865–875PubMedCrossRefGoogle Scholar
  72. 72.
    Haslett C (1999) Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am J Respir Crit Care Med 160: S5–S11PubMedGoogle Scholar
  73. 73.
    Lesur O, Kokis A, Hermans C, et al (2000) Interleukin-2 involvement in early acute respiratory distress syndrome: relationship with polymorphonuclear neutrophil apoptosis and patient survival. Crit Care Med 28: 3814–3822PubMedCrossRefGoogle Scholar
  74. 74.
    Dunican A, Leuenroth SJ, Grutkoski P, et al (2000) TNFalpha-induced suppression of PMN apoptosis is mediated through interleukin-8 production. Shock 14: 284–288PubMedCrossRefGoogle Scholar
  75. 75.
    Aggarwal A, Baker CS, Evans TW, Haslam PL (2000) G-CSF and IL-8 but not GM-CSF correlate with severity of pulmonary neutrophilia in acute respiratory distress syndrome. Eur Respir J 15: 895–901PubMedCrossRefGoogle Scholar
  76. 76.
    Hashimoto S, Kobayashi A, Kooguchi K, 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: 237–243PubMedGoogle Scholar
  77. 77.
    Burdon D, Tiedje T, Pfeffer K et al (2000) The role of tumor necrosis factor in the development of multiple organ failure in a murine model. Crit Care Med 28: 1962–1967PubMedCrossRefGoogle Scholar
  78. 78.
    Grigg JM, Savill JS, Sarraf C, et al (1991) Neutrophil apoptosis and clearance from neonatal lungs. Lancet 338: 720–722PubMedCrossRefGoogle Scholar
  79. 79.
    Cox G, Crossley J, Xing Z (1995) Macrophage engulfment of apoptotic neutrophils contributes to the resolution of acute pulmonary inflammation in vivo. Am J Respir Cell Mol Biol 12: 232–237PubMedGoogle Scholar
  80. 80.
    Savill J, Haslett C (1995) Granulocyte clearance by apoptosis in the resolution of inflammation. Semin Cell Biol 6: 385–393PubMedCrossRefGoogle Scholar
  81. 81.
    Whyte MK, Meagher LC, MacDermot J, Haslett C (1993) Impairment of function in aging neutrophils is associated with apoptosis. J Immunol 150: 5124–5134PubMedGoogle Scholar
  82. 82.
    Meagher LC, Savill JS, Baker A, et al (1992) Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2. J Leukoc Biol 52: 269–273PubMedGoogle Scholar
  83. 83.
    Dransfield I, Stocks SC, Haslett C (1995) Regulation of cell adhesion molecule expression and function associated with neutrophil apoptosis. Blood 85: 3264–3273PubMedGoogle Scholar
  84. 84.
    Carson WE, Yu H, Dierksheide J, Pfeffer K, et al (1999) A fatal cytokine-induced systemic inflammatory response reveals a critical role for NK cells. J Immunol 162: 4943–4951PubMedGoogle Scholar
  85. 85.
    Hagimoto N, Kuwano K, Miyazaki H, et al (1997) Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen. Am J Respir Cell Mol Biol 17: 272–278PubMedGoogle Scholar
  86. 86.
    Chapman HA (1999) A Fas pathway to pulmonary fibrosis. J Clin Invest 104: 1–2PubMedCrossRefGoogle Scholar
  87. 87.
    Kuwano K, Hagimoto N, Kawasaki M, et al (1999) Essential roles of the Fas-Fas ligand pathway in the development of pulmonary fibrosis. J Clin Invest 104: 13–19PubMedCrossRefGoogle Scholar
  88. 88.
    Aoshiba K, Yasui S, Tamaoki J, Nagai A (2000) The Fas/Fas-ligand system is not required for bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 162: 695–700PubMedGoogle Scholar
  89. 89.
    Oberholzer A, Harter L, Feilner A, et al (2000) Differential effect of caspase inhibition on proinflammatory cytokine release in septic patients. Shock 14: 253–257PubMedCrossRefGoogle Scholar
  90. 90.
    Karima R, Matsumoto S, Higashi H, Matsushima K (1999) The molecular pathogenesis of endotoxic shock and organ failure. Mol Med Today 5: 123–132PubMedCrossRefGoogle Scholar
  91. 91.
    Li. P., Allen H, Banerjee S, et al (1995) Mice deficient in IL-1 beta-converting enzyme are defective in production of mature IL-1 beta and resistant to endotoxic shock. Cell 80: 401–411PubMedCrossRefGoogle Scholar
  92. 92.
    Liu P, Anderson RGW (1995) Compartmentalized production of ceramide at the cell surface. J Biol Chem 45: 27129–27185Google Scholar
  93. 93.
    Zundel W, Swiersz LM, Giaccia A (2000) Caveolin 1-mediated regulation of receptor tyrosine kinase-associated phosphatidylinositol 3-kinase activity by ceramide. Mol Cell Biol 20: 1507–1514PubMedCrossRefGoogle Scholar
  94. 94.
    Dreyfuss D, Saumon G (1998) Ventilator-induced lung injury. Lessons from experimental studies. Am J Respir Crit Care Med 157: 294–323PubMedGoogle Scholar
  95. 95.
    Slutsky AS (1999) Lung injury caused by mechanical ventilation. Chest 116: 95–155CrossRefGoogle Scholar
  96. 96.
    Uhlig S, Uhlig U (2001) Molecular mechanisms of pro-inflammatory responses in overventilated lungs. Recent Res Devel Resp Critical Care Med 1: 49–58Google Scholar
  97. 97.
    The Acute Respiratory Distress Syndrome Network (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342: 1301–1308CrossRefGoogle Scholar
  98. 98.
    Held H-D, Boettcher S, Hamann L, Uhlig S (2001) Ventilation-induced chemokine and cytokine release is associated with activation of NFkB and is blocked by steroids. Am J Respir Crit Care Med 163: 711–716PubMedGoogle Scholar
  99. 99.
    Edwards YS (2001) Stretch stimulation: its effects on alveolar type II cell function in the lung. Comp Biochem Physiol A Mol Integr Physiol 129: 245–260PubMedCrossRefGoogle Scholar
  100. 100.
    Imai Y, Kajikawa O, Frevert C, et al (2001) Injurious ventilation strategies enhance organ apoptosis in rabbits. Am J Respir Crit Care Med 163: A677Google Scholar
  101. 101.
    Barkett M, Gilmore TD (1999) Control of apoptosis by Rel/NF-kB transcription factors. Oncogene 18: 6910–6924PubMedCrossRefGoogle Scholar
  102. 102.
    Matute-Bello G, Liles WC, Radella F, et al (1997) Neutrophil apoptosis in the acute respiratory distress syndrome. Am J Respir Crit Care Med 156: 1969–1977PubMedGoogle Scholar
  103. 103.
    Matute-Bello G, Liles WC, Radella F, 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: 1–7PubMedCrossRefGoogle Scholar
  104. 104.
    Wohin L, Uhlig S, Niising R, Wendel A (2001) Granulocyte-macrophage colony-stimulating factor amplifies lipopolysaccharide-induced bronchoconstriction by a neutrophil-and cyclooxygenase 2-dependent mechanism. Am J Respir Crit Care Med 163: 443–450Google Scholar
  105. 105.
    Verhoef G, Boogaerts M (1991) Treatment with granulocyte-macrophage colony stimulating factor and the adult respiratory distress syndrome. Am J Hematol 36: 285–287PubMedCrossRefGoogle Scholar
  106. 106.
    Demuynck H, Zachee P, Verhoef GE, et al (1995) Risks of rhG-CSF treatment in drug-induced agranulocytosis. Ann Hematol 70: 143–147PubMedCrossRefGoogle Scholar
  107. 107.
    Görgen I, Hartung T, Leist M, et al (1992) G-CSF treatment protects rodents against LPS-induced toxicity via suppression of systemic TNF-a. J Immunol 1992: 918–924Google Scholar
  108. 108.
    Tiegs G, Barsig J, Matiba B, et al (1994) Potentiation by granulocyte macrophage colony-stimulating factor of lipopolysaccharide toxicity in mice. J Clin Invest 93: 2616–2424PubMedCrossRefGoogle Scholar
  109. 109.
    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
  110. 111.
    Albertine KH, Wang Z, McIntyre TM, Zimmermann GA (2001) Fas/Fas ligand interaction is associated with epithelial cell injury in ARDS. Am J Respir Crit Care Med 163:A306Google Scholar
  111. 111.
    Parsey MV, Kaneko D, Shenkar R, Abraham E (1999) Neutrophil apoptosis in the lung after hemorrhage or endotoxemia: apoptosis and migration are independent of interleukin-lb. Chest 116:67S–68SPubMedCrossRefGoogle Scholar
  112. 112.
    Xing Z, Gauldie J, Cox G, et al (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101: 311–320PubMedCrossRefGoogle Scholar
  113. 113.
    Klosterhalfen B, Hauptmann S, Offner FA, et al (1997) Induction of heat shock protein 70 by zinc-bis-(DL-hydrogenaspartate) reduces cytokine liberation, apoptosis, and mortality rate in a rat model of LD100 endotoxemia. Shock 7: 254–262PubMedCrossRefGoogle Scholar
  114. 114.
    Cox G (1996) IL-10 enhances resolution of pulmonary inflammation in vivo by promoting apoptosis of neutrophils. Am J Physiol 271: L566–L571PubMedGoogle Scholar
  115. 115.
    Duffy AJ, Nolan B, Sheth K, et al (2000) Inhibition of alveolar neutrophil immigration in endotoxemia is macrophage inflammatory protein 2 independent. J Surg Res 90: 51–57PubMedCrossRefGoogle Scholar

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© Springer-Verlag Italia, Milano 2002

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  • S. Uhlig
  • D. Burdon

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