title: Hyporesponsiveness of donor cells to lipopolysaccharide stimulation reduces the severity of experimental idiopathic pneumonia syndrome: potential role for a gut-lung axis of inflammation.
abstract: Idiopathic pneumonia syndrome (IPS) is a major complication of allogeneic bone marrow transplantation (BMT). We have shown that experimental IPS is associated with increased levels of LPS and TNF-alpha in the bronchoalveolar lavage (BAL) fluid. We hypothesized that the deleterious effects of these inflammatory mediators in the lung may be linked to gut injury that develops after BMT. To test this hypothesis, we used mouse strains that differ in their sensitivity to LPS as donors in an experimental BMT model. Lethally irradiated C3FeB6F(1) hosts received BMT from either LPS-sensitive or LPS-resistant donors. Five weeks after BMT, LPS-resistant BMT recipients had significantly less lung injury compared with recipients of LPS-sensitive BMT. This effect was associated with reductions in TNF-alpha secretion (both in vitro and in vivo), BAL fluid LPS levels, and intestinal injury. The relationship between TNF-alpha, gut toxicity, and lung injury was examined further by direct cytokine blockade in vivo; systemic neutralization of TNF-alpha resulted in a significant reduction in gut histopathology, BAL fluid LPS levels, and pulmonary dysfunction compared with control-treated animals. We conclude that donor resistance to endotoxin reduces IPS in this model by decreasing the translocation of LPS across the intestinal border and systemic and pulmonary TNF-alpha production. These data demonstrate a potential etiologic link between gut and lung damage after BMT and suggest that methods that reduce inflammatory responses to LPS, and specifically, those that protect the integrity of the gut mucosa, may be effective in reducing IPS after BMT.
authors.affiliation: Departments of Internal Medicine and Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109, USA. krcooke@umich.edu
authors.forename: K R
authors.initials: KR
authors.lastname: Cooke
authors.forename: G R
authors.initials: GR
authors.lastname: Hill
authors.forename: A
authors.initials: A
authors.lastname: Gerbitz
authors.forename: L
authors.initials: L
authors.lastname: Kobzik
authors.forename: T R
authors.initials: TR
authors.lastname: Martin
authors.forename: J M
authors.initials: JM
authors.lastname: Crawford
authors.forename: J P
authors.initials: JP
authors.lastname: Brewer
authors.forename: J L
authors.initials: JL
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology*; D007519:Isoantigens / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000633:toxicity; D008168:Lung / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D047889:Receptors, Tumor Necrosis Factor, Type II; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: D015703:Antigens, CD; D007141:Immunoglobulin Fc Fragments; D007519:Isoantigens; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha