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: Anne B Lipke, Gustavo Matute-Bello, Raquel Herrero, Venus A Wong, Stephen M Mongovin, Thomas R Martin
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 301 Issue 1 Pg. L60-70 (Jul 2011) ISSN: 1522-1504 [Electronic] United States
• PMID: 21515659 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Chemokines
• Fas protein, mouse
• Interleukin-1
• Lipopolysaccharides
• Receptors, Death Domain
• Receptors, Interleukin-1
• Receptors, Tumor Necrosis Factor, Type I
• Receptors, Tumor Necrosis Factor, Type II
• Tumor Necrosis Factor-alpha
• fas Receptor
• keratinocyte-derived chemokines

Topics

• Animals
• Apoptosis
• Chemokines (biosynthesis)
• Hyperthermia, Induced
• Interleukin-1 (metabolism)
• Lipopolysaccharides
• Lung (metabolism, pathology)
• Lung Injury (complications, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Pneumonia (complications, metabolism, pathology)
• Receptors, Death Domain (metabolism)
• Receptors, Interleukin-1 (metabolism)
• Receptors, Tumor Necrosis Factor, Type I (metabolism)
• Receptors, Tumor Necrosis Factor, Type II (metabolism)
• Signal Transduction
• Survival Analysis
• Tumor Necrosis Factor-alpha (biosynthesis)
• fas Receptor (metabolism)