AM Choi and J Alam
Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

Accumulating evidence suggests that oxidative stress plays a central role in the pathogenesis of many pulmonary diseases including adult respiratory distress syndrome, emphysema, asthma, bronchopulmonary dysplasia, and interstitial pulmonary fibrosis. The morbidity and mortality of these diseases remain high even with optimal medical management. In our attempts to devise new therapies for these disorders, it is crucial to improve our understanding of the basic mechanism(s) of oxidant-induced lung injury. A major line of investigation seeks to characterize the cellular and molecular responses of the lung to oxidant insults. Much progress has been made in our understanding of the role of the "classic" antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione peroxidase) in mediating the lung's resistance against oxidant lung injury. However, it is becoming clear that other oxidant-induced gene products may also play vital roles in the lung's adaptive and/or protective response to oxidative stress. One such stress-response protein is heme oxygenase-1, HO-1. Since the identification of HO-1 in 1968, many of the studies involving this enzyme were understandably focused on the regulation and function of HO-1 in heme metabolism. This emphasis is self-evident as HO-1 catalyzes the first and rate-limiting step in heme degradation. Interestingly, however, evidence accumulated over the past 25 years demonstrates that HO-1 is induced not only by the substrate heme but also by a variety of non-heme inducers such as heavy metals, endotoxin, heat shock, inflammatory cytokines, and prostaglandins. The chemical diversity of HO-1 inducers led to the speculation that HO-1, besides its role in heme degradation, may also play a vital function in maintaining cellular homeostasis. Further support for this hypothesis was provided by Tyrrell and colleagues who showed in 1989 that HO-1 is also highly induced by a variety of agents causing oxidative stress. Subsequently, many investigators have focused their attention on the function and regulation of HO-1 in various in vitro and in vivo models of oxidant-mediated cellular and tissue injury. The magnitude of HO-1 induction after oxidative stress and the wide distribution of this enzyme in systemic tissues coupled with the intriguing biological activities of the catalytic byproducts, carbon monoxide, iron, and bilirubin, makes HO-1 a highly attractive and interesting candidate stress-response protein which may play key role(s) in mediating protection against oxidant-mediated lung injury. This review will focus on the current understanding of the physiological significance of HO-1 induction and the molecular regulation of HO-1 gene expression in response to oxidative stress. We hope that this discussion will stimulate interest and investigations into a field which is still largely uncharted in the pulmonary research community.

This article has been cited by other articles:

				A. L. Lagan, G. J. Quinlan, S. Mumby, D. D. Melley, P. Goldstraw, G. J. Bellingan, M. R. Hill, D. Briggs, P. Pantelidis, R. M. du Bois, et al. Variation in Iron Homeostasis Genes Between Patients With ARDS and Healthy Control Subjects Chest, June 1, 2008; 133(6): 1302 - 1311. [Abstract] [Full Text] [PDF]

				H. Ozkan, H. Oren, M. Tatli, H. Ates, A. Kumral, and N. Duman Erythroid Apoptosis in Idiopathic Neonatal Jaundice Pediatrics, May 1, 2008; 121(5): e1348 - e1351. [Abstract] [Full Text] [PDF]

				H. Zhao, R. J. Wong, T. C. Doyle, N. Nayak, H. J. Vreman, C. H. Contag, and D. K. Stevenson Regulation of Maternal and Fetal Hemodynamics by Heme Oxygenase in Mice Biol Reprod, April 1, 2008; 78(4): 744 - 751. [Abstract] [Full Text] [PDF]

				J. C. Lee, F. Bhora, J. Sun, G. Cheng, E. Arguiri, C. C. Solomides, S. Chatterjee, and M. Christofidou-Solomidou Dietary flaxseed enhances antioxidant defenses and is protective in a mouse model of lung ischemia-reperfusion injury Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L255 - L265. [Abstract] [Full Text] [PDF]

				F. Tamion, V. Richard, S. Renet, and C. Thuillez Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1308 - G1314. [Abstract] [Full Text] [PDF]

				D. Datta, O. Dormond, A. Basu, D. M. Briscoe, and S. Pal Heme oxygenase-1 modulates the expression of the anti-angiogenic chemokine CXCL-10 in renal tubular epithelial cells Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1222 - F1230. [Abstract] [Full Text] [PDF]

				C.-C. Hong, C. B. Ambrosone, J. Ahn, J.-Y. Choi, M. L. McCullough, V. L. Stevens, C. Rodriguez, M. J. Thun, and E. E. Calle Genetic Variability in Iron-Related Oxidative Stress Pathways (Nrf2, NQ01, NOS3, and HO-1), Iron Intake, and Risk of Postmenopausal Breast Cancer Cancer Epidemiol. Biomarkers Prev., September 1, 2007; 16(9): 1784 - 1794. [Abstract] [Full Text] [PDF]

				A. Goldberg, M. Parolini, B. Y. Chin, E. Czismadia, L. E. Otterbein, F. H. Bach, and H. Wang Toll-like receptor 4 suppression leads to islet allograft survival FASEB J, September 1, 2007; 21(11): 2840 - 2848. [Abstract] [Full Text] [PDF]

				B. Lu, L. Kerepesi, L. Wisse, K. Hitchman, and Q. R. Meng Cytotoxicity and Gene Expression Profiles in Cell Cultures Exposed to Whole Smoke from Three Types of Cigarettes Toxicol. Sci., August 1, 2007; 98(2): 469 - 478. [Abstract] [Full Text] [PDF]

				N Grion, E M Repetto, Y Pomeraniec, C M. Calejman, F Astort, R Sanchez, O P Pignataro, P Arias, and C B Cymeryng Induction of nitric oxide synthase and heme oxygenase activities by endotoxin in the rat adrenal cortex: involvement of both signaling systems in the modulation of ACTH-dependent steroid production J. Endocrinol., July 1, 2007; 194(1): 11 - 20. [Abstract] [Full Text] [PDF]

				S. D. McCarter, S. H. J. Mei, P. F. H. Lai, Q. W. Zhang, C. H. Parker, R. S. Suen, R. D. Hood, Y. D. Zhao, Y. Deng, R. N. N. Han, et al. Cell-based Angiopoietin-1 Gene Therapy for Acute Lung Injury Am. J. Respir. Crit. Care Med., May 15, 2007; 175(10): 1014 - 1026. [Abstract] [Full Text] [PDF]

				A. Abu-Bakar, V. Lamsa, S. Arpiainen, M. R. Moore, M. A. Lang, and J. Hakkola Regulation of CYP2A5 Gene by the Transcription Factor Nuclear Factor (Erythroid-Derived 2)-Like 2 Drug Metab. Dispos., May 1, 2007; 35(5): 787 - 794. [Abstract] [Full Text] [PDF]

				S. W. Ryter, D. Morse, and A. M. K. Choi Carbon Monoxide and Bilirubin: Potential Therapies for Pulmonary/Vascular Injury and Disease Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 175 - 182. [Abstract] [Full Text] [PDF]

				J. Alam and J. L. Cook How Many Transcription Factors Does It Take to Turn On the Heme Oxygenase-1 Gene? Am. J. Respir. Cell Mol. Biol., February 1, 2007; 36(2): 166 - 174. [Abstract] [Full Text] [PDF]

				M. Rokushima, K. Omi, A. Araki, Y. Kyokawa, N. Furukawa, F. Itoh, K. Imura, K. Takeuchi, M. Okada, I. Kato, et al. A Toxicogenomic Approach Revealed Hepatic Gene Expression Changes Mechanistically Linked to Drug-Induced Hemolytic Anemia Toxicol. Sci., February 1, 2007; 95(2): 474 - 484. [Abstract] [Full Text] [PDF]

				S. Zelenay, A. Chora, M. P. Soares, and J. Demengeot Heme oxygenase-1 is not required for mouse regulatory T cell development and function Int. Immunol., January 1, 2007; 19(1): 11 - 18. [Abstract] [Full Text] [PDF]

				J. P. Evans, F. Xu, M. Sirisawad, R. Miller, L. Naumovski, and P. R. O. de Montellano Motexafin Gadolinium-Induced Cell Death Correlates with Heme oxygenase-1 Expression and Inhibition of P450 Reductase-Dependent Activities Mol. Pharmacol., January 1, 2007; 71(1): 193 - 200. [Abstract] [Full Text] [PDF]

				R. Stocker and M. A. Perrella Heme Oxygenase-1: A Novel Drug Target for Atherosclerotic Diseases? Circulation, November 14, 2006; 114(20): 2178 - 2189. [Full Text] [PDF]

				S. Basuroy, S. Bhattacharya, D. Tcheranova, Y. Qu, R. F. Regan, C. W. Leffler, and H. Parfenova HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-{alpha} in cerebral vascular endothelial cells Am J Physiol Cell Physiol, November 1, 2006; 291(5): C897 - C908. [Abstract] [Full Text] [PDF]

				T. Sato, M. Takeno, K. Honma, H. Yamauchi, Y. Saito, T. Sasaki, H. Morikubo, Y. Nagashima, S. Takagi, K. Yamanaka, et al. Heme Oxygenase-1, a Potential Biomarker of Chronic Silicosis, Attenuates Silica-induced Lung Injury Am. J. Respir. Crit. Care Med., October 15, 2006; 174(8): 906 - 914. [Abstract] [Full Text] [PDF]

				Y.-S. Keum, S. Yu, P. P.-J. Chang, X. Yuan, J.-H. Kim, C. Xu, J. Han, A. Agarwal, and A.-N. T. Kong Mechanism of Action of Sulforaphane: Inhibition of p38 Mitogen-Activated Protein Kinase Isoforms Contributing to the Induction of Antioxidant Response Element-Mediated Heme Oxygenase-1 in Human Hepatoma HepG2 Cells. Cancer Res., September 1, 2006; 66(17): 8804 - 8813. [Abstract] [Full Text] [PDF]

				J. Wan and D. Diaz-Sanchez Phase II Enzymes Induction Blocks the Enhanced IgE Production in B Cells by Diesel Exhaust Particles. J. Immunol., September 1, 2006; 177(5): 3477 - 3483. [Abstract] [Full Text] [PDF]

				Y. Drechsler, A. Dolganiuc, O. Norkina, L. Romics, W. Li, K. Kodys, F. H. Bach, P. Mandrekar, and G. Szabo Heme Oxygenase-1 Mediates the Anti-Inflammatory Effects of Acute Alcohol on IL-10 Induction Involving p38 MAPK Activation in Monocytes J. Immunol., August 15, 2006; 177(4): 2592 - 2600. [Abstract] [Full Text] [PDF]

				A. Raddatz, D. Kubulus, J. Winning, I. Bauer, S. Pradarutti, B. Wolf, S. Kreuer, and H. Rensing Dobutamine Improves Liver Function after Hemorrhagic Shock through Induction of Heme Oxygenase-1 Am. J. Respir. Crit. Care Med., July 15, 2006; 174(2): 198 - 207. [Abstract] [Full Text] [PDF]

				S. T. Qureshi, X. Zhang, E. Aberg, N. Bousette, A. Giaid, P. Shan, R. M. Medzhitov, and P. J. Lee Inducible Activation of TLR4 Confers Resistance to Hyperoxia-Induced Pulmonary Apoptosis. J. Immunol., April 15, 2006; 176(8): 4950 - 4958. [Abstract] [Full Text] [PDF]

				S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]

				J. M. Clark, C. J. Lambertsen, R. Gelfand, and A. B. Troxel Optimization of oxygen tolerance extension in rats by intermittent exposure J Appl Physiol, March 1, 2006; 100(3): 869 - 879. [Abstract] [Full Text] [PDF]

				S. W. Chung, Y.-H. Chen, S.-F. Yet, M. D. Layne, and M. A. Perrella Endotoxin-Induced Down-Regulation of Elk-3 Facilitates Heme Oxygenase-1 Induction in Macrophages J. Immunol., February 15, 2006; 176(4): 2414 - 2420. [Abstract] [Full Text] [PDF]

				M. Hill, V. Pereira, C. Chauveau, R. Zagani, S. Remy, L. Tesson, D. Mazal, L. Ubillos, R. Brion, K. Ashgar, et al. Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase FASEB J, December 1, 2005; 19(14): 1957 - 1968. [Abstract] [Full Text] [PDF]

				Y. Jin and A. M. K. Choi Cytoprotection of Heme Oxygenase-1/Carbon Monoxide in Lung Injury Proceedings of the ATS, October 1, 2005; 2(3): 232 - 235. [Abstract] [Full Text] [PDF]

				V. Nascimento-Silva, M. A. Arruda, C. Barja-Fidalgo, C. G. Villela, and I. M. Fierro Novel lipid mediator aspirin-triggered lipoxin A4 induces heme oxygenase-1 in endothelial cells Am J Physiol Cell Physiol, September 1, 2005; 289(3): C557 - C563. [Abstract] [Full Text] [PDF]

				V L Kinnula Focus on antioxidant enzymes and antioxidant strategies in smoking related airway diseases Thorax, August 1, 2005; 60(8): 693 - 700. [Abstract] [Full Text] [PDF]

				Y. Lu, X. Wang, and A. I. Cederbaum Lipopolysaccharide-induced liver injury in rats treated with the CYP2E1 inducer pyrazole Am J Physiol Gastrointest Liver Physiol, August 1, 2005; 289(2): G308 - G319. [Abstract] [Full Text] [PDF]

				K. Minamoto, H. Harada, V. N. Lama, M. A. Fedarau, and D. J. Pinsky Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase J. Exp. Med., July 18, 2005; 202(2): 283 - 294. [Abstract] [Full Text] [PDF]

				N. Wijayanti, T. Kietzmann, and S. Immenschuh Heme Oxygenase-1 Gene Activation by the NAD(P)H Oxidase Inhibitor 4-(2-Aminoethyl) Benzenesulfonyl Fluoride via a Protein Kinase B, p38-dependent Signaling Pathway in Monocytes J. Biol. Chem., June 10, 2005; 280(23): 21820 - 21829. [Abstract] [Full Text] [PDF]

				H. Christou, N. Bailey, M. S. Kluger, S. A. Mitsialis, and S. Kourembanas Extracellular acidosis induces heme oxygenase-1 expression in vascular smooth muscle cells Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2647 - H2652. [Abstract] [Full Text] [PDF]

				B. J. Day and C. Kariya A Novel Class of Cytochrome P450 Reductase Redox Cyclers: Cationic Manganoporphyrins Toxicol. Sci., May 1, 2005; 85(1): 713 - 719. [Abstract] [Full Text] [PDF]

				T. M. Brusko, C. H. Wasserfall, A. Agarwal, M. H. Kapturczak, and M. A. Atkinson An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells J. Immunol., May 1, 2005; 174(9): 5181 - 5186. [Abstract] [Full Text] [PDF]

				S. Dhakshinamoorthy, A. K. Jain, D. A. Bloom, and A. K. Jaiswal Bach1 Competes with Nrf2 Leading to Negative Regulation of the Antioxidant Response Element (ARE)-mediated NAD(P)H:Quinone Oxidoreductase 1 Gene Expression and Induction in Response to Antioxidants J. Biol. Chem., April 29, 2005; 280(17): 16891 - 16900. [Abstract] [Full Text] [PDF]

				T. Miralem, Z. Hu, M. D. Torno, K. M. Lelli, and M. D. Maines Small Interference RNA-mediated Gene Silencing of Human Biliverdin Reductase, but Not That of Heme Oxygenase-1, Attenuates Arsenite-mediated Induction of the Oxygenase and Increases Apoptosis in 293A Kidney Cells J. Biol. Chem., April 29, 2005; 280(17): 17084 - 17092. [Abstract] [Full Text] [PDF]

				F. van Bel, V. Latour, H. J. Vreman, R. J. Wong, D. K. Stevenson, P. Steendijk, J. Egberts, and T. G. Krediet Is carbon monoxide-mediated cyclic guanosine monophosphate production responsible for low blood pressure in neonatal respiratory distress syndrome? J Appl Physiol, March 1, 2005; 98(3): 1044 - 1049. [Abstract] [Full Text] [PDF]

				X. Liu, J. Wei, D. H. Peng, M. D. Layne, and S.-F. Yet Absence of Heme Oxygenase-1 Exacerbates Myocardial Ischemia/Reperfusion Injury in Diabetic Mice Diabetes, March 1, 2005; 54(3): 778 - 784. [Abstract] [Full Text] [PDF]

				S. W. Chung, Y.-H. Chen, and M. A. Perrella Role of Ets-2 in the Regulation of Heme Oxygenase-1 by Endotoxin J. Biol. Chem., February 11, 2005; 280(6): 4578 - 4584. [Abstract] [Full Text] [PDF]

				R. Foresti, M. Hoque, D. Monti, C. J. Green, and R. Motterlini Differential Activation of Heme Oxygenase-1 by Chalcones and Rosolic Acid in Endothelial Cells J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 686 - 693. [Abstract] [Full Text] [PDF]

				J. Wang, L. Lad, T. L. Poulos, and P. R. O. de Montellano Regiospecificity Determinants of Human Heme Oxygenase: DIFFERENTIAL NADPH- AND ASCORBATE-DEPENDENT HEME CLEAVAGE BY THE R183E MUTANT J. Biol. Chem., January 28, 2005; 280(4): 2797 - 2806. [Abstract] [Full Text] [PDF]

				K. Sankaranarayanan and A. K. Jaiswal Nrf3 Negatively Regulates Antioxidant-response Element-mediated Expression and Antioxidant Induction of NAD(P)H:Quinone Oxidoreductase1 Gene J. Biol. Chem., December 3, 2004; 279(49): 50810 - 50817. [Abstract] [Full Text] [PDF]

				P. J. Barnes Mediators of Chronic Obstructive Pulmonary Disease Pharmacol. Rev., December 1, 2004; 56(4): 515 - 548. [Abstract] [Full Text] [PDF]

				J. S. Neto, A. Nakao, K. Kimizuka, A. J. Romanosky, D. B. Stolz, T. Uchiyama, M. A. Nalesnik, L. E. Otterbein, and N. Murase Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide Am J Physiol Renal Physiol, November 1, 2004; 287(5): F979 - F989. [Abstract] [Full Text] [PDF]

				C. L. Hartsfield, I. F. McMurtry, D. D. Ivy, K. G. Morris, S. Vidmar, D. M. Rodman, and K. A. Fagan Cardioprotective and vasomotor effects of HO activity during acute and chronic hypoxia Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2009 - H2015. [Abstract] [Full Text] [PDF]

				D. Kubulus, F. Roesken, M. Amon, M. Rucker, M. Bauer, I. Bauer, and M. D. Menger Mechanism of the delay phenomenon: tissue protection is mediated by heme oxygenase-1 Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2332 - H2340. [Abstract] [Full Text] [PDF]

				J. Wang, F. Niemevz, L. Lad, L. Huang, D. E. Alvarez, G. Buldain, T. L. Poulos, and P. R. O. de Montellano Human Heme Oxygenase Oxidation of 5- and 15-Phenylhemes J. Biol. Chem., October 8, 2004; 279(41): 42593 - 42604. [Abstract] [Full Text] [PDF]

				H. Fujimoto, M. Ohno, S. Ayabe, H. Kobayashi, N. Ishizaka, H. Kimura, K.-i. Yoshida, and R. Nagai Carbon Monoxide Protects Against Cardiac Ischemia--Reperfusion Injury In Vivo via MAPK and Akt--eNOS Pathways Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1848 - 1853. [Abstract] [Full Text] [PDF]

				H. Zhou, F. Lu, C. Latham, D. S. Zander, and G. A. Visner Heme Oxygenase-1 Expression in Human Lungs with Cystic Fibrosis and Cytoprotective Effects against Pseudomonas Aeruginosa In Vitro Am. J. Respir. Crit. Care Med., September 15, 2004; 170(6): 633 - 640. [Abstract] [Full Text] [PDF]

				R. Kaarteenaho-Wiik and V. L. Kinnula Distribution of Antioxidant Enzymes in Developing Human Lung, Respiratory Distress Syndrome, and Bronchopulmonary Dysplasia J. Histochem. Cytochem., September 1, 2004; 52(9): 1231 - 1240. [Abstract] [Full Text] [PDF]

				N. Li, J. Alam, M. I. Venkatesan, A. Eiguren-Fernandez, D. Schmitz, E. Di Stefano, N. Slaughter, E. Killeen, X. Wang, A. Huang, et al. Nrf2 Is a Key Transcription Factor That Regulates Antioxidant Defense in Macrophages and Epithelial Cells: Protecting against the Proinflammatory and Oxidizing Effects of Diesel Exhaust Chemicals J. Immunol., September 1, 2004; 173(5): 3467 - 3481. [Abstract] [Full Text] [PDF]

				M. A. Arruda, A. G. Rossi, M. S. de Freitas, C. Barja-Fidalgo, and A. V. Graca-Souza Heme Inhibits Human Neutrophil Apoptosis: Involvement of Phosphoinositide 3-Kinase, MAPK, and NF-{kappa}B J. Immunol., August 1, 2004; 173(3): 2023 - 2030. [Abstract] [Full Text] [PDF]

				M. L. Jison, P. J. Munson, J. J. Barb, A. F. Suffredini, S. Talwar, C. Logun, N. Raghavachari, J. H. Beigel, J. H. Shelhamer, R. L. Danner, et al. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease Blood, July 1, 2004; 104(1): 270 - 280. [Abstract] [Full Text] [PDF]

				R. S. Bhat, M. Bhaskaran, A. Mongia, N. Hitosugi, and P. C. Singhal Morphine-induced macrophage apoptosis: oxidative stress and strategies for modulation J. Leukoc. Biol., June 1, 2004; 75(6): 1131 - 1138. [Abstract] [Full Text] [PDF]

				S. C. McAllister, S. G. Hansen, R. A. Ruhl, C. M. Raggo, V. R. DeFilippis, D. Greenspan, K. Fruh, and A. V. Moses Kaposi sarcoma-associated herpesvirus (KSHV) induces heme oxygenase-1 expression and activity in KSHV-infected endothelial cells Blood, May 1, 2004; 103(9): 3465 - 3473. [Abstract] [Full Text] [PDF]

				S. J. Gibbons and G. Farrugia The role of carbon monoxide in the gastrointestinal tract J. Physiol., April 15, 2004; 556(2): 325 - 336. [Abstract] [Full Text] [PDF]

				E. M. Sikorski, T. Hock, N. Hill-Kapturczak, and A. Agarwal The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury Am J Physiol Renal Physiol, March 1, 2004; 286(3): F425 - F441. [Abstract] [Full Text] [PDF]

S. Gebel, B. Gerstmayer, A. Bosio, H.-J. Haus