Ablation of tumor necrosis factor receptor type I (p55) alters oxygen-induced lung injury

Hyperoxic lung injury, believed to be mediated by reactive oxygen species, inflammatory cell activation, and release of cytotoxic cytokines, complicat es the care of many critically ill patients. The cytokine tumor necrosis fa ctor (TNF)-alpha is induced in lungs exposed to high concentrations of oxyg en; however, its contribution to hyperoxia-induced lung injury remains uncl ear. Both TNF-alpha treatment and blockade with anti-TNF antibodies increas ed survival in mice exposed to hyperoxia. In the current study, to determin e if pulmonary oxygen toxicity is dependent on either of the TNF receptors, type I (TNFR-I) or type II (TNFR-II), TNFR-I or TNFR-II gene-ablated [( -/ -)] mice and wild-type control mice (WT; C57BL/6) were studied in >95% oxyg en. There was no difference in average length of survival, although early s urvival was better for TNFR-I(-/-) mice than for either TNFR-II(-/-) or WT mice. At 48 h of hyperoxia, slightly more alveolar septal thickening and pe ribronchiolar and periarteriolar edema were detected in WT than in TNFR-I(- /-) lungs. By 84 h of oxygen exposure, TNFR-I(-/-) mice demonstrated greate r alveolar debris, inflammation, and edema than WT mice. TNFR-I was necessa ry for induction of cytokine interleukin (IL)-1 beta, IL-1 receptor antagon ist, chemokine macrophage inflammatory protein (MIP)-1 beta, MIP-P, interfe ron-gamma-induced protein-10 (IP-10), and monocyte chemoattractant protein (MCP)-1 mRNA in response to intratracheal administration of recombinant mur ine TNF-alpha. However, IL-1 beta, IL-6, macrophage migration inhibitory fa ctor, MIP-1 alpha, MIP-2, and MCP-1 mRNAs were comparably induced by hypero xia in TNFR-I(-/-) and WT lungs. In contrast, mRNA for manganese superoxide dismutase and intercellular adhesion molecule-1 were induced by hyperoxia only in WT mice. Differences in early survival and toxicity suggest that pu lmonary oxygen toxicity is in part mediated by TNFR-I. However, induction o f specific cytokine and chemokine mRNA and lethality in response to severe hyperoxia was independent of TNFR-I expression. The current study supports the prediction that therapeutic efforts to block TNF-alpha receptor functio n will not protect against pulmonary oxygen toxicity.