Heme oxygenase (HO) catalyzes the first and rate limiting step in the degradation of heme to yield equimolar quantities of biliverdin Ixa, carbon monoxide (CO), and iron. HO-1, the inducible isoform, is highly induced by a variety of causing oxidative stress including hydrogen peroxide, glutathione depletors, UV irradiation, endotoxin, and hyperoxia. This diversity of HO-1 inducers has provided further support for the speculation that HO-1, besides its role in heme degradation, may also play a vital function in maintaining cellular homeostasis. Our laboratory and others have demonstrated that induction of HO-1 provides protection both in vivo and in vitro against oxidation stress including hyperoxia. The mechanism(s) by which HO-1 provides protection against oxidative stress is poorly understood. Our recent studies (see Progress Report/Preliminary Studies) highlight the formal possibility that the gaseous molecule CO can mediate the protective effects of HO-1 against oxidant-induced lung injury principally via its anti-inflammatory and anti-apoptotic properties. We therefore hypothesize that CO mediates HO-1 induced cytoprotection against hyperoxic lung injury. Furthermore, we hypothesize that CO mediates the cytoprotection via the p38 mitogen activated protein kinase (MAPK) signaling pathway.
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