© 2007 American Thoracic Society DOI: 10.1165/rcmb.2006-0002ED
Heme Oxygenase-1A Multifaceted Triple-Threat MoleculeBrigham and Women's Hospital, Boston, Massachusetts Heme oxygenase (HO), identified in 1968, was initially described as an enzyme system in microsomes capable of degrading heme to bilirubin (1). Further studies showed that HO was an inducible mono-oxygenase that functions independently of cytochrome p450 (2), and this inducible enzyme was later named HO-1. A second and constitutive member of this enzyme family, HO-2, was subsequently identified (3). Original interest in HO related to its function in erythrocyte turnover and the catabolism of heme, as HO oxidatively cleaves heme to produce carbon monoxide (CO), biliverdin (subsequently converted to bilirubin), and free iron. However, evidence of the heme oxygenase system in organs not involved in erythrocyte turnover led to speculation that HO enzymes may function beyond a degradation process. More recent excitement has revolved around the multifaceted properties of HO enzymes, not only their ability to catabolize the pro-oxidant heme but also the ability of heme degradation products to have important biological functions (thus the concept of triple threat). Of the two enzymes, HO-1 is ubiquitously expressed in most cell types, and the gene encoding HO-1 is highly regulated at the level of gene transcription by a number of physical and chemical stimuli (4). The reviews published in this issue of the AJRCMB will focus on the HO-1 enzyme. This series will cover a number of HO-1–related issues, including its role in the biology of pulmonary diseases (5), and provide a deeper understanding of how the gene is transcriptionally regulated (6). Overview of gene regulation will go beyond the traditional interaction of transcription factors with their cognate DNA binding sites in the HO-1 promoter, but will also consider the functional genetic polymorphisms in the human HO-1 gene promoter that modulate the level of transcriptional activity and the magnitude by which HO-1 responds to a pathophysiologic stimulus. These polymorphisms may associate with an altered risk profile for disease (5). For many years, CO and bilirubin were regarded as toxic waste products of the HO reaction. However, in 1987, a beneficial role of bilirubin was proposed, based on the in vitro antioxidant activities of the pigment (7). Moreover, it had long been known that heme degradation led to the production of the endogenous gas molecule CO, yet the majority of research focused on another gas molecule, nitric oxide. Over the last decade, the interest in the biological role of CO has gained interest and momentum in the research arena. During this same time period, the interest in HO has shifted from a metabolic to a protective function of the enzyme and its products of heme catabolism in a variety of conditions associated with oxidative stress. Thus, this review series will also cover the topic of CO and bilirubin, and their roles as potential therapeutic agents in pulmonary disease (8). We hope that the articles in this series will provide further insight, and generate additional interest, in this multifaceted molecule. We also hope that the concepts learned in prior investigations, and research yet to come, will lead to an impact of the HO system (either through gene transfer [9] or the administration of CO/bilirubin [8]) on our approach to human disease in the future. Acknowledgments The author thanks Dr. Augustine M. K. Choi and Dr. Stella Kourembanas for their advice and helpful suggestions regarding this review series, and all the authors of the articles in this series. Also, the author thanks Dr. Steven D. Shapiro for accepting the contribution of these articles to the AJRCMB. Footnotes Conflict of Interest Statement: M.A.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. References
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