Protective Effects of Heme Oxygenase-1 in Acute Lung Injury

Abstract

Heme oxygenase (HO) catalyzes the first and rate-limiting step in the oxidative degradation of heme to bilirubin 1 Choi AMK Alam J Heme oxygenase-1: function, regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996; 15: 9-19 Crossref PubMed Scopus (1006) Google Scholar , 2 Maines MD The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997; 37: 517-554 Crossref PubMed Scopus (2195) Google Scholar (Fig 1) . The binding of HO with the heme molecule leads to the cleavage of a meso carbon bond and results in the production of biliverdin, which is subsequently converted to bilirubin by biliverdin reductase. 1 Choi AMK Alam J Heme oxygenase-1: function, regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996; 15: 9-19 Crossref PubMed Scopus (1006) Google Scholar , 2 Maines MD The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997; 37: 517-554 Crossref PubMed Scopus (2195) Google Scholar Three isoforms of HO exist; HO-1 is highly inducible, while HO-2 and HO-3 are constitutively expressed. 1 Choi AMK Alam J Heme oxygenase-1: function, regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996; 15: 9-19 Crossref PubMed Scopus (1006) Google Scholar , 2 Maines MD The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997; 37: 517-554 Crossref PubMed Scopus (2195) Google Scholar Although heme is the major substrate of HO-1, a variety of nonheme products, including heavy metals, cytokines, hormones, endotoxin, and heat shock, are also strong inducers of HO-1 expression. 1 Choi AMK Alam J Heme oxygenase-1: function, regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996; 15: 9-19 Crossref PubMed Scopus (1006) Google Scholar In addition, HO-1 is highly induced by a variety of agents causing oxidative stress, including hydrogen peroxide, glutathione depletors, ultraviolet irradiation, endotoxin, and hyperoxia. 1 Choi AMK Alam J Heme oxygenase-1: function, regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol. 1996; 15: 9-19 Crossref PubMed Scopus (1006) Google Scholar , 2 Maines MD The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997; 37: 517-554 Crossref PubMed Scopus (2195) Google Scholar , 3 Keyse SM Tyrrell RM Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci USA. 1989; 86: 99-103 Crossref PubMed Scopus (1102) Google Scholar , 4 Lee PJ Alam J Sylvester SL et al. Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung injury. Am J Respir Cell Mol Biol. 1996; 14: 556-568 Crossref PubMed Scopus (192) Google Scholar This diversity of HO-1 inducers has provided further support for the speculation that HO-1, besides its role in heme degradation, may also serve to play a vital function in maintaining cellular homeostasis. We will review some of the experimental data that support the evolving paradigm that the stress inducible gene HO-1 plays an important functional role in the lung and host's defense against oxidant-induced lung injury.