title: Death receptors mediate the adverse effects of febrile-range hyperthermia on the outcome of lipopolysaccharide-induced lung injury.
abstract: We have shown that febrile-range hyperthermia enhances lung injury and mortality in mice exposed to inhaled LPS and is associated with increased TNF-α receptor activity, suppression of NF-κB activity in vitro, and increased apoptosis of alveolar epithelial cells in vivo. We hypothesized that hyperthermia enhances lung injury and mortality in vivo by a mechanism dependent on TNF receptor signaling. To test this, we exposed mice lacking the TNF-receptor family members TNFR1/R2 or Fas (TNFR1/R2(-/-) and lpr) to inhaled LPS with or without febrile-range hyperthermia. For comparison, we studied mice lacking IL-1 receptor activity (IL-1R(-/-)) to determine the role of inflammation on the effect of hyperthermia in vivo. TNFR1/R2(-/-) and lpr mice were protected from augmented alveolar permeability and mortality associated with hyperthermia, whereas IL-1R(-/-) mice were susceptible to augmented alveolar permeability but protected from mortality associated with hyperthermia. Hyperthermia decreased pulmonary concentrations of TNF-α and keratinocyte-derived chemokine after LPS in C57BL/6 mice and did not affect pulmonary inflammation but enhanced circulating markers of oxidative injury and nitric oxide metabolites. The data suggest that hyperthermia enhances lung injury by a mechanism that requires death receptor activity and is not directly associated with changes in inflammation mediated by hyperthermia. In addition, hyperthermia appears to enhance mortality by generating a systemic inflammatory response and not by a mechanism directly associated with respiratory failure. Finally, we observed that exposure to febrile-range hyperthermia converts a modest, survivable model of lung injury into a fatal syndrome associated with oxidative and nitrosative stress, similar to the systemic inflammatory response syndrome.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Puget Sound Medical Center, University of Washington, Seattle, Washington 98108, USA. ablipke@u.washington.edu
authors.forename: Anne B
authors.initials: AB
authors.lastname: Lipke
authors.forename: Gustavo
authors.initials: G
authors.lastname: Matute-Bello
authors.forename: Raquel
authors.initials: R
authors.lastname: Herrero
authors.forename: Venus A
authors.initials: VA
authors.lastname: Wong
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Mongovin
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
mesh_terms: D000818:Animals; D017209:Apoptosis; D018925:Chemokines / Q000096:biosynthesis; D006979:Hyperthermia, Induced; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism / Q000473:pathology; D055370:Lung Injury / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000150:complications / Q000378:metabolism / Q000473:pathology; D053218:Receptors, Death Domain / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019014:fas Receptor / Q000378:metabolism
chemical_list: D018925:Chemokines; C491899:Fas protein, mouse; D007375:Interleukin-1; D008070:Lipopolysaccharides; D053218:Receptors, Death Domain; D017472:Receptors, Interleukin-1; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C074302:keratinocyte-derived chemokines