Pathophysiology of Lung Injury After Hematopoietic Stem Cell Transplantation

  • Kenneth R. Cooke
Part of the Contemporary Hematology book series (CH)


Over the last several decades, hematopoietic stem cell transplantation (SCT) has emerged as an important therapeutic option for a number of malignant and nonmalignant conditions. Unfortunately, the utility of this treatment strategy is limited by several side effects, the most serious of which include the development of graft-vs-host disease (GVHD) and pulmonary toxicity. Pulmonary dysfunction, specifically diffuse lung injury, is a major complication of SCT; it occurs in 25–55% of SCT recipients and can account for approximately 50% of transplant-related mortality (1–6). Diffuse lung injury is described as either acute or chronic with respect to both the time of onset after SCT and the tempo of disease progression once the diagnosis has been established. Approximately 50% of the time, an infectious etiology is uncovered, whereas in the remaining 50% of cases, no microbial organisms are identified in the lungs of affected patients (7). In recent years, the judicious use of broad-spectrum antimicrobial prophylaxis has tipped the balance of pulmonary complications after SCT from infectious to noninfectious. In this context, two types of pulmonary dysfunction have been recognized: acute noninfectious lung injury (termed idiopathic pneumonia syndrome [IPS]) and subacute or chronic noninfectious lung injury. Two forms of subacute/chronic lung injury are common in patients over 100 d posttransplant: airflow obstruction and restrictive lung injury (8–16). Each form of noninfectious lung injury is associated with significant morbidity and mortality and, unfortunately, clinical responses to standard therapeutic approaches are limited. This chapter will be devoted to noninfectious lung injury occurring both early and late


  1. 1.
    Clark J, Madtes D, Martin T, et al. Idiopathic pneumonia after bone marrow transplantation: cytokine activation and lipopolysaccharide amplification in the bronchoalveolar compartment. Crit Care Med 1999; 27: 1800.PubMedCrossRefGoogle Scholar
  2. 2.
    Crawford S, Hackman R. Clinical course of idiopathic pneumonia after bone marrow transplantation. Am Rev RespirDis 1993; 147: 1393.Google Scholar
  3. 3.
    Weiner RS, Mortimer MB, Gale RP, et al. Interstitial pneumonitis after bone marrow transplantation. Ann Intern Med 1986; 104: 168–175.PubMedGoogle Scholar
  4. 4.
    Quabeck K. The lung as a critical organ in marrow transplantation. Bone Marrow Transplant 1994; 14: S19 - S28.PubMedGoogle Scholar
  5. 5.
    Crawford S, Longton G, Storb R. Acute graft versus host disease and the risks for idiopathic pneumonia after marrow transplantation for severe aplastic anemia. Bone Marrow Transplant 1993; 12: 225.PubMedGoogle Scholar
  6. 6.
    Kantrow SP, Hackman RC, Boeckh M, et al. Idiopathic pneumonia syndrome: changing spectrum of lung injury after marrow transplantation. Transplantation 1997; 63: 1079–1086.PubMedCrossRefGoogle Scholar
  7. 7.
    Clark J, Hansen J, Hertz M, et al. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev RespirDis 1993; 147: 1601–1606.Google Scholar
  8. 8.
    Holland HK, Wingard JR, Beschorner WE, et al. Bronchiolitis obliterans in bone marrow transplantation and its relationship to chronic graft-versus-host disease and low serum IgG. Blood 1988; 72: 621–627.PubMedGoogle Scholar
  9. 9.
    Schultz KR, Green GJ, Wensley D, et al. Obstructive lung disease in children after allogeneic bone marrow transplantation. Blood 1994; 84: 3212–3220.PubMedGoogle Scholar
  10. 10.
    Crawford SW, Pepe M, Lin D, et al. Abnormalities of pulmonary function tests after marrow transplantation predict nonrelapse mortality. Am J Respir Crit Care Med 1995; 152: 690–695.PubMedGoogle Scholar
  11. 11.
    Sullivan K, Mori M, Sanders J, et al. Late complications of allogeneic and autologous bone marrow transplantation. Bone Marrow Transplant 1992; 10: 127–134.PubMedGoogle Scholar
  12. 12.
    Wiesendanger P, Archimbaud E, Mornex J, et al. Post transplant obstructive lung disease (“broncliolitis obliterans”). Eur Respir J 1995; 8: 551–558.PubMedGoogle Scholar
  13. 13.
    Sanchez J, Torres A, Serrano J, et al. Long term follow up of immunosuppressive treatment for obstructive airway disease after allogeneic bone marrow transplantation. Bone Marrow Transplant 1997; 20: 403–408.PubMedCrossRefGoogle Scholar
  14. 14.
    Badier M, Guillot C, Delpiecre S, et al. Pulmonary function changes 100 days and one year after bone marrow transplantation. Bone Marrow Transplant 1993; 12: 457–461.PubMedGoogle Scholar
  15. 15.
    Quigley P, Yeager A, Loughlin G. The effects of bone marrow transplantation on pulmonary function in children. Pediatr Pulmonary 1994; 18: 361–367.CrossRefGoogle Scholar
  16. 16.
    Abhyankar S, Gilliland DG, Ferrara JLM. Interleukin 1 is a critical effector molecule during cytokine dysregulation in graft-versus-host disease to minor histocompatibility antigens. Transplantation 1993; 56: 1518–1523.PubMedCrossRefGoogle Scholar
  17. 17.
    Yousem SA. The histological spectrum of pulmonary graft-versus-host disease in bone marrow transplant recipients. Hum Pathol 1995; 26: 668–675.PubMedCrossRefGoogle Scholar
  18. 18.
    Neiman P, Wasserman PB, Wentworth BB, et al. Interstitial pneumonia and cytomegalovirus infection as complications of human marrow transplantation. Transplantation 1973; 15: 478–485.PubMedCrossRefGoogle Scholar
  19. 19.
    Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset non-infectious pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 28: 425–434.PubMedCrossRefGoogle Scholar
  20. 20.
    Yanik G, Hellerstedt B, Custer J, et al. Etanercept as a novel therapy for idiopathic pneumonia syndrome after allogenic bone marrow transplantation. Biol Blood Marrow Transplant 2002; 8: 395–400.PubMedCrossRefGoogle Scholar
  21. 21.
    Wingard JR, Mellits ED, Sostrin MB, et al. Interstitial pneumonitis after allogeneic bone marrow transplantation. Nine-year experience at a single institution. Medicine 1988; 67: 175–186.PubMedCrossRefGoogle Scholar
  22. 22.
    Weiner RS, Horowitz MM, Gale RP, et al. Risk factors for interstitial pneumonitis following bone marrow transplantation for severe aplastic anemia. Br J Haematol 1989; 71: 535.PubMedCrossRefGoogle Scholar
  23. 23.
    Meyers JD, Flournoy N, Thomas ED. Nonbacterial pneumonia after allogeneic marrow transplantation: a review of ten years’ experience. Rev Infect Dis 1982; 4: 1119–1132.PubMedCrossRefGoogle Scholar
  24. 24.
    Atkinson K, Turner J, Biggs JC, et al. An acute pulmonary syndrome possibly representing acute graft-versushost disease involving the lung interstitium. Bone Marrow Transplant 1991; 8: 231.PubMedGoogle Scholar
  25. 25.
    Della Volpe A, Ferreri AJ, Annaloro C, et al. Lethal pulmonary complications significantly correlate with individually assessed mean lung dose in patients with hematologic malignancies treated with total body irradiation. Int J Radiat Oncol Biol Phys 2002; 52: 483–488.PubMedCrossRefGoogle Scholar
  26. 26.
    Robbins RA, Linder J, Stahl MG, et al. Diffuse alveolar hemorrhage in autologous bone marrow transplant recipients. Am JMed 1989; 87: 511–518.Google Scholar
  27. 27.
    Lewis ID, DeFor T, Weisdorf DJ. Increasing incidence of diffuse alveolar hemorrhage following allogeneic bone marrow transplantation: cryptic etiology and uncertain therapy. Bone Marrow Transplant 2000; 26: 539–543.PubMedCrossRefGoogle Scholar
  28. 28.
    MetcalfJP, Rennard SI, Reed EC, et al. Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. University of Nebraska Medical Center Bone Marrow Transplant Group. Am J Med 1994; 96: 327–334.PubMedCrossRefGoogle Scholar
  29. 29.
    Capizzi SA, Kumar S, Huneke NE, et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2001; 27: 1299–1303.PubMedCrossRefGoogle Scholar
  30. 30.
    Wilczynski SW, Erasmus JJ, Petros WP, et al. Delayed pulmonary toxicity syndrome following high-dose chemotherapy and bone marrow transplantation for breast cancer. Am JRespir Grit Care Med 1998; 157: 565–573.Google Scholar
  31. 31.
    Bhalla KS, Wilczynski SW, Abushamaa AM, et al. Pulmonary toxicity of induction chemotherapy prior to standard or high-dose chemotherapy with autologous hematopoietic support. Am J Respir Crit Care Med 2000; 161: 17–25.PubMedGoogle Scholar
  32. 32.
    Kelley J. Cytokines of the lung. Am Rev Respir Dis 1990; 141: 765–788.PubMedCrossRefGoogle Scholar
  33. 33.
    Piguet P, Collart M, Grau G, et al. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature 1990; 344: 245–247.PubMedCrossRefGoogle Scholar
  34. 34.
    Schmidt J, Pliver CN, Lepe-Zuniga JL, et al. Silica-stimulated monocytes release fibroblast proliferation factors identical to interleukin-1. A potential role for interleukin-1 in the pathogenesis of silicosis. J Clin Invest 1984; 73: 1462–1472.PubMedCrossRefGoogle Scholar
  35. 35.
    Suter P, Suter S, Girardin E, et al. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock or sepsis. Am Rev Resp Dis 1992; 145: 1016.PubMedCrossRefGoogle Scholar
  36. 36.
    Hyers T, Tricomi S, Dettenmier P, et al. Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome. Am Rev Respir Dis 1991; 144: 268.PubMedCrossRefGoogle Scholar
  37. 37.
    Bortin M, Ringden O, Horowitz M, et al. Temporal relationships between the major complications of bone marrow transplantation for leukemia. Bone Marrow Transplant 1989; 4: 339.PubMedGoogle Scholar
  38. 38.
    Beschorner W, Saral R, Hutchins G, et al. Lymphocytic bronchitis associated with graft versus host disease in recipients of bone marrow transplants. N Engl J Med 1978; 299: 1030–1036.PubMedCrossRefGoogle Scholar
  39. 39.
    Piguet PF, Grau GE, Collart MA, et al. Pneumopathies of the graft-versus-host reaction. Alveolitis associated with an increased level of tumor necrosis factor MRNA and chronic interstitial pneumonitis. Lab Invest 1989; 61: 37–45.PubMedGoogle Scholar
  40. 40.
    Clark JG, Madtes DK, Hackman RC, et al. Lung injury induced by alloreactive Thl cells is characterized by host-derived mononuclear cell inflammation and activation of alveolar macrophages. J Immunol 1998; 161: 1913–1920.PubMedGoogle Scholar
  41. 41.
    Shankar G, Bryson J, Jennings C, et al. Idiopathic pneumonia syndrome in mice after allogeneic bone marrow transplantation. Am J Respir Cell Mol Biol 1998; 18: 235–242.PubMedGoogle Scholar
  42. 42.
    Cooke KR, Kobzik L, Martin TR, et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation. I. The roles of minor H antigens and endotoxin. Blood 1996; 8: 3230–3239.Google Scholar
  43. 43.
    Cooke KR, Krenger W, Hill GR, et al. Host reactive donor T cells are associated with lung injury after experimental allogeneic bone marrow transplantation. Blood 1998; 92: 2571–2580.PubMedGoogle Scholar
  44. 44.
    Nestel FP, Price KS, Seemayer TA, et al. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med 1992; 175: 405–413.PubMedCrossRefGoogle Scholar
  45. 45.
    Piguet PF, Grau GE, Allet B, et al. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-versus-host disease. J Exp Med 1987; 166: 1280–1289.PubMedCrossRefGoogle Scholar
  46. 46.
    Antin JH, FerraraJLM. Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80: 2964–2968.PubMedGoogle Scholar
  47. 47.
    Braun YM, Lowin B, French L, et al. Cytotoxic T cells deficient in both functional Fas ligand and perforin show residual cytolytic activity yet lose their capacity to induce lethal acute graft-versus-host disease. J Exp Med 1996; 183: 657–661.PubMedCrossRefGoogle Scholar
  48. 48.
    Baker MB, Altman NH, Podack ER, et al. The role of cell-mediated cytotoxicity in acute GVHD after MHCmatched allogeneic bone marrow transplantation in mice. J Exp Med 1996; 183: 2645–2656.PubMedCrossRefGoogle Scholar
  49. 49.
    Fegan C, Poynton C, Whittaker J. The gut mucosal barrier in bone marrow transplantation. Bone Marrow Transplant 1990; 5: 373–377.PubMedGoogle Scholar
  50. 50.
    Jackson SK, Parton J, Barnes RA, et al. Effect of IgM-enriched intravenous immunoglobulin (Pentaglobulin) on endotoxaemia and anti-endotoxin antibodies in bone marrow transplantation. Eur J Clin Invest 1993; 23: 540–545.PubMedCrossRefGoogle Scholar
  51. 51.
    Hill GR, Crawford JM, Cooke KJ, et al. Total body irradiation effects on acute graft versus host disease. The role of gastrointestinal damage and inflammatory cytokines. Blood 1997; 90 pp. 3204–3213.PubMedGoogle Scholar
  52. 52.
    Cooke K, Hill G, Crawford J, et al. Tumor necrosis factor-a production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft versus host disease. JClinlnvest 1998; 102: 1882–1891.Google Scholar
  53. 53.
    Hill GR, Teshima T, Rebel VI, et al. The p55 TNF-alpha receptor plays a critical role in T cell alloreactivity. J Immunol 2000; 164: 656–663.PubMedGoogle Scholar
  54. 54.
    Cooke K, Gerbitz A, Hill G, et al. LPS Antagonism reduces graft-versus-host disease and preserves graftversus-leukemia activity after experimental bone marrow transplantation. J Clin Invest 2001; 7: 1581–1589.CrossRefGoogle Scholar
  55. 55.
    Milburn HJ, Poulter LW, Prentice HG, et al. Pulmonary cell populations in recipients of bone marrow transplants with interstitial pneumonitis. Thorax 1989; 44: 570.PubMedCrossRefGoogle Scholar
  56. 56.
    Milburn HJ, Du Bois RM, Prentice HG, et al. Pneumonitis in bone marrow transplant recipients results from a local immune response. Clin Exp Immunol 1990; 81: 232.PubMedCrossRefGoogle Scholar
  57. 57.
    Schwarer AP, Hughes JMB, Trotman-Dickenson B, et al. A chronic pulmonary syndrome associated with graft-versus-host disease after allogeneic marrow transplantation. Transplantation 1992; 54: 1002–1008.PubMedCrossRefGoogle Scholar
  58. 58.
    Sutedja TG, Apperley JF, Hughes JMB, et al. Pulmonary function after bone marrow transplantation for chronic myeloid leukemia. Thorax 1988; 43: 163–169.PubMedCrossRefGoogle Scholar
  59. 59.
    Sloane J, Depledge M, Powles R, et al. Histopathology of the lung after bone marrow transplantation. J Clin Pathol 1983; 36: 546–554.PubMedCrossRefGoogle Scholar
  60. 60.
    Hackman RC, Sale GE. Large airway inflammation as a possible manifestation of a pulmonary graft-versushost reaction in bone marrow allograft recipients. Lab Invest 1981; 44: 26A.Google Scholar
  61. 61.
    Connor R, Ramsay N, McGlave P, et al. Pulmonary pathology in bone marrow transplant recipients. Lab Invest 1982; 46: 3.Google Scholar
  62. 62.
    Madtes DK, Crawford SW. Lung injuries associated with graft-versus-host reactions. In: Ferrara JLM, Deeg HJ, Burakoff SJ, eds. Graft-vs.-Host Disease. New York: Marcel Dekker, 1997: 425.Google Scholar
  63. 63.
    Beaumont F, Schilizzi BM, Kallenberg CG, et al. Expression of class II-MHC antigens on alveolar and bronchiolar epithelial cells in fibrosing alveolitis. Chest 1986; 89: 136.CrossRefGoogle Scholar
  64. 64.
    Kunkel SL, Strieter RM. Cytokine networking in lung inflammation. Hosp Prac 1990:63–76 Vol 10 pp. 6366, 69 73–76.Google Scholar
  65. 65.
    Teshima T, Ordemann R, Reddy P, et al. Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nature Med 2002; 8: 575–581.PubMedCrossRefGoogle Scholar
  66. 66.
    Jordana M, Richards C, Irving LB, et al. Spontaneous in vitro release of alveolar-macrophage cytokines after the intratracheal instillation of bleomycin in rats. Am Rev Respir Dis 1988; 137: 1135–1140.PubMedGoogle Scholar
  67. 67.
    Fattal-German M, Le Roy Ladurie F, et al. Expression of ICAM-1 and TNF alpha in human alveolar macrophages from lung-transplant recipients. Ann NYAcad Sci 1996; 796: 138–148.CrossRefGoogle Scholar
  68. 68.
    Sumitomo M, Sakiyama S, Tanida N, et al. Difference in cytokine production in acute and chronic rejection of rat lung allografts. Transplant Int 1996; 9: S223 - S225.CrossRefGoogle Scholar
  69. 69.
    Stephens KE, Ishizaka A, Larrick JW, et al. Tumor necrosis factor causes increased pulmonary permeability and edema. Comparison to septic acute lung injury. Am Rev Respir Dis 1988; 137: 1364–1370.PubMedGoogle Scholar
  70. 70.
    Curtis JL, Byrd PK, Warnock ML, et al. Requirement of CD4-positive T cells for cellular recruitment to the lungs of mice in response to a particulate intratracheal antigen. J Clin Invest 1991; 88: 1244.PubMedCrossRefGoogle Scholar
  71. 71.
    Toews GB. Pulmonary dendritic cells: sentinels of lung associated lymphoid tissues. Am J Respir Cell Mol Biol 1991; 4: 204.PubMedGoogle Scholar
  72. 72.
    Rabinowich H, Zeevi A, Paradis IL, et al. Proliferative responses of bronchoalveolar lavage lymphocytes from heart-lung transplant patients. Transplantation 1990; 49: 115.PubMedCrossRefGoogle Scholar
  73. 73.
    Curtis DJ, Smale A, THien F, et al. Chronic airflow obstruction in long-term survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant 1995; 16: 169–173.PubMedGoogle Scholar
  74. 74.
    Clark JG, Schwartz DA, Flournoy N, et al. Risk factors for air-flow obstruction in recipients of bone marrow transplants. Ann Intern Med 1987; 107: 648–656.PubMedGoogle Scholar
  75. 75.
    Urbanski SJ, Kossakowska AE, Curtis J, et al. Idiopathic small airways pathology in patients with graftversus-host disease following allogeneic bone marrow transplantation. Am J Surg Pathol 1987; 11: 965.PubMedCrossRefGoogle Scholar
  76. 76.
    Wyatt SE, Nunn P, Hows JM, et al. Airways obstruction associated with graft-versus-host disease after bone marrow transplantation. Thorax 1984; 39: 887.PubMedCrossRefGoogle Scholar
  77. 77.
    Hakim FT, Mackall CL. The immune system: effector and target of graft-versus-host disease. In: FerraraJLM, Deeg HJ, Burakoff SJ, eds. Graft-vs.-Host Disease. New York: Marcel Dekker, 1997: 257.Google Scholar
  78. 78.
    Hattori K, Hirano T, Miyajima H, et al. Differential effects of anti-fas ligand and anti-tumor necrosis factor a antibodies on acute graft-versus-host disease pathologies. Blood 1998; 91: 4051–4055.PubMedGoogle Scholar
  79. 79.
    Workman D, Clancy JJ. Interstitial pneumonitis and lymphocytic bronchiolitis/bronchitis as a direct result of acute lethal graft-versus-host disease duplicate the histopathology of lung allograft rejection. Transplantation 1994; 58: 207.PubMedGoogle Scholar
  80. 80.
    Panoskaltsis-Mortari A, Taylor PA, Yaegar TM, et al. The critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogenic recipients are due to donor T cell infusion and potentiated by cyclophoshamide. J Clin Invest 1997; 100: 1015–1027.PubMedCrossRefGoogle Scholar
  81. 81.
    Cooke K, Hill G, Gerbitz A, et al. TNFa neutralization reduces lung injury after experimental allogeneic bone marrow transplantation. Transplantation 2000; 70: 272–279.PubMedCrossRefGoogle Scholar
  82. 82.
    Cooke K, Hill G, Gerbitz A, et al. Hyporesponsiveness of donor cells to LPS stimulation reduces the severity of experimental idiopathic pneumonia syndrome: potential role for a gut-lung axis of inflammation. Jlmmunol 2000; 165: 6612–6619.Google Scholar
  83. 83.
    Cooke K, Kobzik L, Teshima T, et al. A role for Fas-Fas ligand but not perforin mediated cytolysis in the development of experimental idiopathic pneumonia syndrome. Blood 2000; 96: 768a.Google Scholar
  84. 84.
    Gerbitz A, Wilke A, Eissner G, et al. Critical role for CD54 (ICAM-1) in the development of experimental indiopathic pneumonia syndrome. Blood 2000; 96: 768a.Google Scholar
  85. 85.
    Jasinski M, Wieckiewicz J, Ruggiero I, et al. Isotype-specific regulation of MHC Class II gene expression in human monocytes by exogenous and endogenous tumor necrosis factor. J Clin Immunol 1995; 15: 185.PubMedCrossRefGoogle Scholar
  86. 86.
    Smith S, Skerrett S, Chi E, et al. The locus of tumor necrosis factor-a action in lung inflammation. Am JRespir Cell Mol Biol 1998; 19: 881.Google Scholar
  87. 87.
    Vallera DA, Taylor PA, Vannice JL, et al. Interleukin-1 or tumor necrosis factor-alpha antagonists do not inhibit graft-versus-host disease induced across the major histocompatibility barrier in mice. Transplantation 1995; 60: 1371–1374.PubMedGoogle Scholar
  88. 88.
    Clark JG, Mandac JB, Dixon AE, et al. Neutralization of tumor necrosis factor-alpha action delays but does not prevent lung injury induced by alloreactive T helper 1 cells. Transplantation 2000; 70: 39–43.PubMedGoogle Scholar
  89. 89.
    Haddad I, Ingbar D, Panoskaltsis-Mortari A, et al. Activated alveolar macrophage-derived nitric oxide predicts the development of lung damage after marrow transplantation in mice. Chest 1999; 116: 37S.Google Scholar
  90. 90.
    Haddad I, Panoskaltsis-Mortari A, Ingbar D, et al. High levels of peroxynitrite are generated in the lungs of irradiated mice given cyclophosphamide and allogeneic T cells: a potential mechanism of injury after marrow transplantation. Am J Respir Cell Mol Biol 1999; 20: 1125.PubMedGoogle Scholar
  91. 91.
    Christ W, Asano O, Robidoux A, et al. E5531, a pure endotoxin antagonist of high potency. Science 1995; 268: 80–83.PubMedCrossRefGoogle Scholar
  92. 92.
    Garbrecht B, Di Silvio M, Demetris A, et al. Tumor necrosis factor-a regulates in vivo nitric oxide synthesis and induces liver injury during endotoxemia. Hepatology 1994; 20: 1055.CrossRefGoogle Scholar
  93. 93.
    Freudenberg M, Galanos C. Tumor necrosis factor alpha mediates lethal activity of killed gram-negative and gram-positive bacteria in D-galactosamine treated mice. Infect Immun 1991; 59: 2110.Google Scholar
  94. 94.
    Crawford J. Cellular and molecular biology of the inflamed liver. Curr Opin Gastroenterol 1997; 13: 175.CrossRefGoogle Scholar
  95. 95.
    Matuschak G, Pinksy M, Klein E, et al. Effects of D-galactosamine induced acute liver injury on mortality and pulmonary responses to Escherichia coli lipopolysaccharide. Am Rev Respir Dis 1990; 141: 1296.PubMedGoogle Scholar
  96. 96.
    Matuschak GM, Mattingly ME, Tredway TL, et al. Liver-lung interactions during E. coli endotoxemia. Am J Respir Crit Care Med 1994; 149: 41–49.PubMedGoogle Scholar
  97. 97.
    Nakao A, Taki S, Yasui M, et al. The fate of intravenously injected endotoxin in normal rats and in rats with liver failure. Hepatology 1994; 19: 1251.PubMedCrossRefGoogle Scholar
  98. 98.
    Lehmann V, Freudenberg M, Galanos C. Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine treated mice. J Exp Med 1987; 165: 657.PubMedCrossRefGoogle Scholar
  99. 99.
    Galanos C, Freudenber M, Reutter W. Galactosamine induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci USA 1987; 76: 5939.CrossRefGoogle Scholar
  100. 100.
    Katz M, Grosfeld J, Gross K. Impaired bacterial clearance and trapping in obstructive jaundice. Am J Surg 1984;199 Vol 199 pp. 14–20.Google Scholar
  101. 101.
    Holler E, Kolb HJ, Moller A, et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood 1990; 75: 1011–1016.PubMedGoogle Scholar
  102. 102.
    Borin M, Ringden O, Horowitz M, et al. Temporal relationship between the major complications of bone marrow transplantation for leukemia. Bone Marrow Transplant 1989; 4: 339.Google Scholar
  103. 103.
    Martin T, Rubenfeld G, Ruzinski J. 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 1997; 155: 937.PubMedGoogle Scholar
  104. 104.
    Martin T, Goodman R. The role of chemokines in the pathophysiology of the acute respiratory distress syndrome (ARDS). In: Hebert C, ed. Chemokines in Disease. Totowa, NJ: Humana, 1999: 81–110.CrossRefGoogle Scholar
  105. 105.
    DiGiovine B, Lynch J, Martinez F, et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8. J Immunol 1996; 157: 4194–5202.PubMedGoogle Scholar
  106. 106.
    Ruse GC, Andersson BA, Kjellstrom C, et al. Persistent high BAL fluid granulocyte activation marker levels as early indicators of bronchiolitis obliterans after lung transplant. Eur Respir J 1999; 14: 1123–1130.CrossRefGoogle Scholar
  107. 107.
    Zheng L, Walters EH, Ward C, et al. Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation. Thorax 2000; 55: 53–59.PubMedCrossRefGoogle Scholar
  108. 108.
    Reynaud-Gaubert M, Thomas P, Badier M, et al. Early detection of airway involvement in obliterative bronchiolitis after lung transplantation. Functional and bronchoalveolar lavage cell findings. Am J Respir Crit Care Med 2000; 161: 1924–1929.PubMedGoogle Scholar
  109. 109.
    Elssner A, Vogelmeier C. The role of neutrophils in the pathogenesis of obliterative bronchiolitis after lung transplantation. Transplant Infect Dis 2001; 3: 168–176.CrossRefGoogle Scholar
  110. 110.
    St John RC, GadekJE, Tutschka PJ, et al. Analysis of airflow obstruction by bronchoalveolar lavage following bone marrow transplantation. Implications for pathogenesis and treatment. Chest 1990; 98: 600–607.PubMedCrossRefGoogle Scholar
  111. 111.
    Urbanski SJ, Kossakowska AE, Curtis J, et al. Idiopathic small airways pathology in patients with graftversus-host disease following allogeneic bone marrow transplantation. Am J Surg Pathol 1987; 11: 965–971.PubMedCrossRefGoogle Scholar
  112. 112.
    Glode LM, Rosenstreich DL. Genetic control of B cell activation by bacterial lipopolysaccaride is mediated by multiple distinct genes or alleles. J Immunol 1976; 117: 2061–2066.PubMedGoogle Scholar
  113. 113.
    Poltorak A, Ziaolong H, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/20ScCr mice: mutations in T1r4 gene. Science 1998; 282: 2085.Google Scholar
  114. 114.
    Watson J, Kelly K, Largen M, et al. The genetic mapping of a defective LPS response gene in C3H/Hej mice. J Immunol 1978; 120: 422–424.PubMedGoogle Scholar
  115. 115.
    Sultzer BM, Castagna R, Bandeakar J, et al. Lipopolysaccharide nonresponder cells: the C3H/HeJ defect. Immunobiology 1993; 187: 257–271.PubMedCrossRefGoogle Scholar
  116. 116.
    Cooke K, Olkiewicz K, Clouthier S, et al. Critical role for CD14 and the innate immune response in the induction of experimental acute graft-versus-host disease. Blood 2001; 98: 776a.Google Scholar
  117. 117.
    Shlomchik W, Couzens M, Tang C, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999; 285: 412–415.PubMedCrossRefGoogle Scholar
  118. 118.
    Watanabe T, Kawamura T, Kawamura H, et al. Intermediate TCR cells in mouse lung. Their effector function to induce pneumonitis in mice with autoimmune-like graft-versus-host disease. J Immunol 1997; 158: 5805.PubMedGoogle Scholar
  119. 119.
    Chen W, Chatta K, Rubin W, et al. Polymorphic segments of CD45 can serve as targets for GVHD and GVL responses. Blood 1995; 86 (suppl): 158a.Google Scholar
  120. 120.
    Gartner JG, Merry AC, Smith CI. An analysis of pulmonary natural killer cell activity in Fl-hybrid mice with acute graft-versus-host reactions. Transplantation 1988; 46: 879–886.PubMedCrossRefGoogle Scholar
  121. 121.
    Leblond V, Zouabi H, Sutton L, et al. Late CD8+ lymphocytic alveolitis after allogeneic bone marrow transplantation and chronic graft-versus-host disease. Am J Crit Care Med 1994; 150: 1056.Google Scholar
  122. 122.
    Trauth BC, Klas C, Peters AM, et al. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science 1989; 245: 301–305.PubMedCrossRefGoogle Scholar
  123. 123.
    Itoh N, Yonehara S, Ishii A, et al. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 1991; 66: 233–243.PubMedCrossRefGoogle Scholar
  124. 124.
    Lowin B, Hahne M, Mattmann C, et al. Cytolytic T-cell cytotoxicity is mediated through perforM and Fas lytic pathways. Nature (London) 1994; 370: 650–652.CrossRefGoogle Scholar
  125. 125.
    Lee RK, Spielman J, Zhao DY. PerforM fas ligand and tumor necrosis factor are the major cytotoxic molecules used by lymphokine-activated killer cells. J Immunol 1996; 157: 1919–1925.PubMedGoogle Scholar
  126. 126.
    Teshima T, Hill G, Pan L, et al. IL-11 separates graft-versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest 1999; 104: 317–325.PubMedCrossRefGoogle Scholar
  127. 127.
    Blazar B, Taylor P, Vallera D. CD4+ and CD8+ T cells each can utilize a perform -dependent pathway to mediate lethal graft versus host disease in major histocompatibility complex-disparate recipients. Transplantation 1997; 64: 571–576.PubMedCrossRefGoogle Scholar
  128. 128.
    Rafi AQ, Zeytun A, Bradley M, et al. Evidence for the Involvement of Fas ligand and perforM in the induction of vascular leak syndrome. J Immunol 1998; 161: 3077–3086.PubMedGoogle Scholar
  129. 129.
    Matute-Bello G, Liles WC, Steinberg KP, et al. Soluble Fas ligand induces epithelial cell apoptosis in humans with acute lung injury (ARDS). Jlmmunol 1999; 163: 2217–2225.Google Scholar
  130. 130.
    Hiroyasu S, Shiraishi M, Koji T, et al. Analysis of Fas system in pulmonary injury of graft-versus-host disease after rat intestinal transplantation. Transplantation 1999; 68: 933–938.PubMedCrossRefGoogle Scholar
  131. 131.
    Hashimoto S, Kobayashi A, Kooguchi K, et al. Upregulation of two death pathways of perforin/granzyme and FasL/Fas in septic acute respiratory distress syndrome. Am J Respir Crit Care Med 2000; 161: 237–243.PubMedGoogle Scholar
  132. 132.
    Massard G, Tongiio MW, Wihlm JM, et al. The dendritic cell lineage: an ubiquitous antigen-presenting organization. Ann Thorac Surg 1996; 61: 252.PubMedCrossRefGoogle Scholar
  133. 133.
    Armstrong LR, Christensen PJ, Paine R, et al. Regulation of the immunostimulatory activity of rat pulmonary interstitial dendritic cells by cell-cell interactions and cytokines. Am J Repir Cell Mol Biol 1994; 11: 682.Google Scholar
  134. 134.
    Dupuis M, McDonald DM. Dendritic-cell regulation of lung immunity. Am J Respir Cell Mol Biol 1997; 17: 284.PubMedGoogle Scholar
  135. 135.
    Christensen PJ, Armstrong LR, Fak JJ, et al. Regulation of rat pulmonary dendritic cell immunostimulatory activity by alveolar epithelial cell-derived granulocyte macrophage colony-stimulating factor. Am J Respir Cell Mol Biol 1995; 13: 426.PubMedGoogle Scholar
  136. 136.
    van Haarst JM, de Wit HJ, Drexhage HA, et al. Distribution and immunophenotype of mononuclear and dendritic cells in the human lung. Am J Respir Cell Mol Biol 1994; 10: 487.PubMedGoogle Scholar
  137. 137.
    Yousem SA, Ray L, Paradis IL, et al. Potential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation. Ann Thorac Surg 1990; 49: 424.PubMedCrossRefGoogle Scholar
  138. 138.
    Ferrara JLM, Deeg HJ. Graft versus host disease. N Engl J Med 1991; 324: 667–674.PubMedCrossRefGoogle Scholar
  139. 139.
    Kradin RL, Xia W, Pike M, et al. Interleukin-2 promotes the motility of dendritic cells and their accumulation in lung and skin. Pathobiology 1996; 64: 180.PubMedCrossRefGoogle Scholar
  140. 140.
    Suda T, Callahan RJ, Wilkerson RA, et al. Interferon-gamma reduces Ia+ dendritic cells traffic to the lung. J Leukocyte Biol 1996; 60: 519.PubMedGoogle Scholar
  141. 141.
    Mackay CR. Chemokines: immunology’s high impact factors. Nature Immunol 2001; 2: 95–101.CrossRefGoogle Scholar
  142. 142.
    Luster AD. Chemokines-chemotactic cytokines that mediate inflammation. N Engl J Med 1998; 338: 436–445.PubMedCrossRefGoogle Scholar
  143. 143.
    Rollins BJ. Chemokines. Blood 1997; 90: 909–928.PubMedGoogle Scholar
  144. 144.
    Nelson PJ, Krensky AM. Chemokines, chemokine receptors, and allograft rejection. Immunity 2001; 14: 377–386.PubMedCrossRefGoogle Scholar
  145. 145.
    Gerard C, Rollins BJ. Chemokines and disease. Nature Immunol 2001; 2: 108–115.CrossRefGoogle Scholar
  146. 146.
    Luster AD. The role of chemokines in linking innate and adaptive immunity. Curr Opin Immunol 2002; 14: 129–135.PubMedCrossRefGoogle Scholar
  147. 147.
    Panoskaltsis-Mortari A, Strieter RM, Hermanson JR, et al. Induction of monocyte-and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation. Blood 2000; 96: 834–839.PubMedGoogle Scholar
  148. 148.
    Serody JS, Burkett SE, Panoskaltsis-Mortari A, et al. T-Lymphocyte production of macrophage inflammatory protein-lalpha is critical to the recruitment of CD8(+) T cells to the liver, lung, and spleen during graft-versushost disease. Blood 2000; 96: 2973–2980.PubMedGoogle Scholar
  149. 149.
    Murai M, Yoneyama H, Harada A, et al. Active participation of CCR5(+)CD8(+) T lymphocytes in the pathogenesis of liver injury in graft-versus-host disease. J Clin Invest 1999; 104: 49–57.PubMedCrossRefGoogle Scholar
  150. 150.
    Cerveri I, Fulgoni P, Giorgiani G, et al. Lung function abnormalities after bone marrow transplantation in children: has the trend recently changed? Chest 2001; 120: 1900–1906.PubMedCrossRefGoogle Scholar
  151. 151.
    Ringden O, Remberger M, Ruutu T, et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Blood 1999; 93: 2196–2201.PubMedGoogle Scholar
  152. 152.
    Clark JG, Crawford SW, Madtes DK, et al. Obstructive lung disease after allogeneic marrow transplantation. Clinical presentation and course. Ann Intern Med 1989; 111: 368–376.PubMedGoogle Scholar
  153. 153.
    Ralph DD, Springmeyer SC, Sullivan KM, et al. Rapidly progressive air-flow obstruction in marrow transplant recipients. Possible association between obliterative bronchiolitis and chronic graft-versus-host disease. Am Rev Respir Dis 1984; 129: 641–644.PubMedGoogle Scholar
  154. 154.
    Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Semin Hematol 1991; 28: 250–259.PubMedGoogle Scholar
  155. 155.
    King TE Jr. Overview of bronchiolitis. Clin Chest Med 1993; 14: 607–610.PubMedGoogle Scholar
  156. 156.
    Crawford SW, Clark JG. Bronchiolitis associated with bone marrow transplantation. Clin Chest Med 1993; 14: 741–749.PubMedGoogle Scholar
  157. 157.
    Cooper JD, Billingham M, Egan T, et al. A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts. International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1993; 12: 713–716.PubMedGoogle Scholar
  158. 158.
    Ooi GC, Peh WC, Ip M. High-resolution computed tomography of bronchiolitis obliterans syndrome after bone marrow transplantation. Respiration 1998; 65: 187–191.PubMedCrossRefGoogle Scholar
  159. 159.
    Bankier AA, Van Muylem A, Knoop C, et al. Bronchiolitis obliterans syndrome in heart-lung transplant recipients: diagnosis with expiratory CT. Radiology 2001; 218: 533–539.PubMedGoogle Scholar
  160. 160.
    Beinert T, Dull T, Wolf K, et al. Late pulmonary impairment following allogeneic bone marrow transplantation. Eur J Med Res 1996; 1: 343–348.PubMedGoogle Scholar
  161. 161.
    Depledge MH, Barrett A, Powles RL. Lung function after bone marrow grafting. IntJ Radiat Oncol Biol Phys 1983; 9: 145–151.CrossRefGoogle Scholar
  162. 162.
    Gore EM, Lawton CA, Ash RC, et al. Pulmonary function changes in long-term survivors of bone marrow transplantation. Int J Radiat Oncol Biol Phys 1996; 36: 67–75.PubMedCrossRefGoogle Scholar
  163. 163.
    Tait RC, Burnett AK, Robertson AG, et al. Subclinical pulmonary function defects following autologous and allogeneic bone marrow transplantation: relationship to total body irradiation and graft-versus-host disease. Int J Radiat Oncol Biol Phys 1991; 20: 1219–1227.PubMedCrossRefGoogle Scholar
  164. 164.
    Belperio JA, Keane MP, Burdick MD, et al. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome. J Clin Invest 2001; 108: 547–556.PubMedGoogle Scholar
  165. 165.
    Belperio JA, DiGiovine B, Keane MP, et al. Interleukin-1 receptor antagonist as a biomarker for bronchiolitis obliterans syndrome in lung transplant recipients. Transplantation 2002; 73: 591–599.PubMedCrossRefGoogle Scholar
  166. 166.
    Elssner A, Jaumann F, Dobmann S, et al. Elevated levels of interleukin-8 and transforming growth factor-beta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells. Munich Lung Transplant Group. Transplantation 2000; 70: 362–367.PubMedCrossRefGoogle Scholar
  167. 167.
    El-Gamel A, Sim E, Hasleton P, et al. Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation. J Heart Lung Transplant 1999; 18: 828–837.PubMedCrossRefGoogle Scholar
  168. 168.
    Piguet P, Collart M, Grau G, et al. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med 1989; 170: 655–663.PubMedCrossRefGoogle Scholar
  169. 169.
    Piguet P, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J 1994; 7: 515–518.PubMedCrossRefGoogle Scholar
  170. 170.
    Reynaud-Gaubert M, Thomas P, Gregoire R, et al. Clinical utility of bronchoalveolar lavage cell phenotype analyses in the postoperative monitoring of lung transplant recipients. Eur J Cardiothorac Surg 2002; 21: 60–66.PubMedCrossRefGoogle Scholar
  171. 171.
    Leonard CT, Soccal PM, Singer L, et al. Dendritic cells and macrophages in lung allografts: a role in chronic rejection? Am J Respir Crit Care Med 2000; 161: 1349–1354.PubMedGoogle Scholar
  172. 172.
    Ward C, Whitford H, Snell G, et al. Bronchoalveolar lavage macrophage and lymphocyte phenotypes in lung transplant recipients. J Heart Lung Transplant 2001; 20: 1064–1074.PubMedCrossRefGoogle Scholar
  173. 173.
    Szeto WY, Krasinskas AM, Kreisel D, et al. Donor antigen-presenting cells are important in the development of obliterative airway disease. J Thorac Cardiovasc Surg 2000; 120: 1070–1077.PubMedCrossRefGoogle Scholar
  174. 174.
    Yamada A, Konishi K, Cruz GL, et al. Blocking the CD28–B7 T-cell costimulatory pathway abrogates the development of obliterative bronchiolitis in a murine heterotopic airway model. Transplantation 2000; 69: 743–749.PubMedCrossRefGoogle Scholar
  175. 175.
    Shankar G, Cohen DA. Idiopathic pneumonia syndrome after bone marrow transplantation: the role of pre-transplant radiation conditioning and local cytokine dysregulation in promoting lung inflammation and fibrosis. Int J Exp Pathol 2001; 82: 101–113.PubMedCrossRefGoogle Scholar
  176. 176.
    Coker R, Laurent G. Pulmonary fibrosis: cytokines in the balance. Eur Respir J 1998; 11: 1218–1221.PubMedCrossRefGoogle Scholar
  177. 177.
    Ortiz L, Lasky J, Lungarella G, et al. Upregulation of the p75 but not the p55 TNFa receptor mRNA after silica and bleomycin exposure and protectin from lung injury in double receptor knockout mice. Am J Respir Cell Mol Biol 1999; 20: 825–833.PubMedGoogle Scholar
  178. 178.
    Miyazaki Y, Araki K, Vesin C, et al. Expression of a tumor necrosis factor-a transgene in murine lung causes lymphocytic and fibrosing alveolitis. J Clin Invest 1995; 96: 250–259.PubMedCrossRefGoogle Scholar
  179. 179.
    Payne L, Chan CK, Fyles G, et al. Cyclosporine as possible prophylaxis for obstructive airways disease after allogeneic bone marrow transplantation. Chest 1993; 104: 114–118.PubMedCrossRefGoogle Scholar
  180. 180.
    Whitford H, Walters EH, Levvey B, et al. Addition of inhaled corticosteroids to systemic immunosuppression after lung transplantation: a double-blind, placebo-controlled trial. Transplantation 2002; 73: 1793–1799.PubMedCrossRefGoogle Scholar
  181. 181.
    Rabitsch W, Deviatko E, Keil F, et al. Successful lung transplantation for bronchiolitis obliterans after allogeneic marrow transplantation. Transplantation 2001; 71: 1341–1343.PubMedCrossRefGoogle Scholar
  182. 182.
    Xun CQ, Thompson JS, Jennings CD, et al. Effect of total body irradiation, busulfan—cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood 1994; 83: 2360–2367.PubMedGoogle Scholar
  183. 183.
    O’Garra A, Murphy K. Role of cytokines in determining T-lymphocyte function. Curr Opin Immunol 1994; 6: 458–466.PubMedCrossRefGoogle Scholar
  184. 184.
    Swain SL, Weinberg AD, English M, et al. IL-4 directs the development of Th2-like helper effectors. J Immunol 1990; 145: 3796–3806.PubMedGoogle Scholar
  185. 185.
    Swain SL, Bradley LM, Croft M, et al. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev 1991; 123: 115–144.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2004

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  • Kenneth R. Cooke

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