The Role of Heme Oxygenase-1 in Pulmonary Disease

Abstract

Heme oxygenase (HO)-1, the inducible isoform of heme oxygenase, is a cytoprotective enzyme that plays a central role in the defense against oxidative and inflammatory insults in the lung. HO-1 catalyzes the degradation of heme, a potent oxidant, into biliverdin, iron, and carbon monoxide (CO). These downstream products of heme catabolism have recently been found to mediate the antioxidant, antiapoptotic, antiproliferative, vasodilatory, and anti-inflammatory properties of HO-1. Although absence of HO-1 is rare in humans, a number of HO-1 promoter polymorphisms have been identified that may influence HO-1 expression in vivo and lead to disease states. This review will summarize studies that implicate HO-1 and heme metabolites in the pathophysiology of pulmonary disease and discuss recent advances in the therapeutic applications of HO-1.Keywords: HO-1; polymorphism; ARDS; pulmonary hypertension; COPD THE ROLE OF HEME OXYGENASE-1 IN PULMONARY DISEASEHeme oxygenase (HO)-1, the inducible isoform of heme oxygenase, plays a critical role in defending the lung against inflammatory and oxidant-induced cellular and tissue injury. This cytoprotective enzyme catalyzes the degradation of heme, a potent oxidant, to generate biliverdin-IX␣, iron, and carbon monoxide (CO) (Figure 1) (1). Biliverdin-IX␣ is converted to bilirubin-IX␣, a potent endogenous antioxidant (2), with recently recognized anti-inflammatory properties (3), while iron is sequestered by ferritin, leading to additional antioxidant (4) and antiapoptotic (5) effects. CO has numerous biological functions, including anti-inflammatory properties (6, 7), and shares many similarities with nitric oxide (NO), such as its ability to inhibit smooth muscle cell proliferation (8, 9) and platelet aggregation (10), as well as modulate vascular tone by increasing cGMP levels (11).In the lung, HO-1 is expressed in various cells types, including type II pneumocytes and alveolar macrophages, and is induced by heme (12), hypoxia (13,14), hyperoxia (15), and NO (16), as well as endotoxin and proinflammatory cytokines (e.g., IL-6, (Received in final form September 3, 2006 ) This work was funded by T32 HL007633-21 (L.E.F.), RO1 HL60788 (M.A.P.), and R01 HL55454 (S.A.M.) from the National Institutes of Health.

Hydrogen gas reduces hyperoxic lung injury via the Nrf2 pathway in vivo

“…HO-1 is a rate-limiting anti-inflammatory/antiapoptotic enzyme that catalyzes the conversion of heme into equimolar quantities of biliverdin (further reduced to bilirubin through biliverdin reductase), iron, and carbon monoxide (46). Animal studies have demonstrated that HO-1 plays a critical protective role in several different lung diseases, including ARDS, pulmonary hypertension, asthma, chronic obstructive pulmonary disease (COPD), and hyperoxic lung injury (13). In vivo, exogeneous administration of HO-1 to rats via a recombinant adenovirus significantly attenuated hyperoxic lung injury.…”

“…HO-1, a heme-degrading enzyme, is highly induced by oxidative stress and plays a critical role in defending the lung against inflammatory and oxidant-induced cellular and tissue injury (13,32). HO-1 is induced by a number of signaling pathways and transcription factors (1,41).…”

Overexpression of HO-1 Protects against TNF-α-Mediated Airway Inflammation by Down-Regulation of TNFR1-Dependent Oxidative Stress

“…12 Airway smooth muscle contractility, which can be increased through ROS formation, is inhibited by HO-1 induction. 13 Moreover, the 5Ј-untranslated region of the human HO-1 gene contains many stress-activated response elements, such as antioxidant response elements.…”

Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma

“…HO-1 is the inducible isoform of haem oxygenase and catalyses the degradation of haem, a potent oxidant, to generate biliverdin, iron and carbon monoxide [13]. Biliverdin is converted to bilirubin, a potent endogenous anti-oxidant, while iron is sequestered by ferritin, leading to an additional anti-oxidant effect [13].…”

“…Biliverdin is converted to bilirubin, a potent endogenous anti-oxidant, while iron is sequestered by ferritin, leading to an additional anti-oxidant effect [13]. CO has anti-inflammatory properties [13], suggesting that HO-1 plays a critical role in defending the lung against inflammatory and oxidant-induced cellular and tissue injury and is considered to be a potential therapeutic target in allergic inflammation [14].…”