Role of tumor necrosis factor alpha and its receptor I in preconditioning by hyperoxia.

Hyperoxic pretreatment (>95% O2) can evoke myocardial adaptation to ischemia, a method which is potentially clinically usable. We wanted to investigate the role of tumor necrosis factor alpha (TNFα) and its p55 receptor (receptor I) in signaling of hyperoxic adaptation to ischemia. Mice deficient for TNFα (TNFα -/-) or the TNF receptor I (TNFRI -/-) gene and their wild types were subjected to 60 minutes of hyperoxia or sham treatment. Their lungs were then collected for immunoblotting, their hearts isolated and subjected to global ischemia and reperfusion in a Langendorff system, and aortic rings mounted in organ baths for reactivity studies. Hyperoxia increased expression of TNFα and TNFα converting enzyme in pulmonary proteins from wild type mice, in which hyperoxia increased myocardial tolerance to ischemia. Post–ischemic heart function was improved and infarct size reduced in wild type mice, but not in TNFα -/- or TNFRI -/-. The contractile response to TNFα on aortic rings was attenuated by hyperoxic pretreatment and by TNFRI -/-. Thus we conclude that TNFα, acting through TNFRI, appears important for the protective effects of hyperoxia.