Heme Oxygenase-1 a Critical Arbitrator of Cell Death Pathways in Lung Injury and Disease

摘要

Increases in cell death by programmed (ie., apoptosis, autophagy) or non-programmed mechanisms (ie., necrosis) occur during tissue injury, and may contribute to the etiology of several pulmonary or vascular disease states. The low molecular weight stress protein heme oxygenase-1 (HO-1) confers cytoprotection against cell death in various models of lung and vascular injury by inhibiting apoptosis, inflammation, and cell proliferation. HO-1 serves a vital metabolic function as the rate-limiting step in the heme degradation pathway and in the maintenance of iron homeostasis. The transcriptional induction of HO-1 occurs in response to multiple forms of chemical and physical cellular stress. The cytoprotective functions of HO-1 may be attributed to heme turnover, as well as to beneficial properties of its enzymatic reaction products: biliverdin-IXα, iron, and carbon monoxide (CO). Recent studies have demonstrated that HO-1 or CO inhibits stress-induced extrinsic and intrinsic apoptotic pathways in vitro. A variety of signaling molecules have been implicated in the cytoprotection conferred by HO-1/CO, including autophagic proteins, p38 mitogen activated protein kinase, signal transducer and activator of transcription proteins, nuclear factor-κB, phosphatydylinositol-3-kinase/Akt, and others. Enhanced HO-1 expression or the pharmacological application of HO end-products affords protection in preclinical models of tissue injury, including experimental and transplant-associated ischemia/reperfusion injury, promising potential future therapeutic applications.