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Carbon Monoxide and Bilirubin

Potential Therapies for Pulmonary/Vascular Injury and Disease

Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Stefan W. Ryter, Ph.D., Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, MUH628NW, 3,459 5th Ave, Pittsburgh, PA 15213. E-mail: ryters{at}upmc.edu

Abstract

Heme oxygenase (HO)-1, an inducible, low–molecular-weight stress protein, confers cellular and tissue protection in multiple models of injury and disease, including oxidative or inflammatory lung injury, ischemia/reperfusion (I/R) injuries, and vascular injury/disease. The tissue protection provided by HO-1 potentially relates to the endogenous production of the end products of its enzymatic activity: namely, biliverdin (BV)/bilirubin (BR), carbon monoxide (CO), and iron. Of these, CO and BV/BR show promise as possible therapeutic agents when applied exogenously in models of lung or vascular injury. CO activates intracellular signaling pathways that involve soluble guanylate cyclase and/or p38 mitogen-activated protein kinase. Although toxic at elevated concentrations, low concentrations of CO can confer antiinflammatory, antiapoptotic, antiproliferative, and vasodilatory effects. BV and BR are natural antioxidants that can provide protection against oxidative stress in cell culture and in plasma. Application of BV or BR protects against I/R injury in several organ models. Recent evidence has also demonstrated antiinflammatory and antiproliferative properties of these pigments. To date, evidence has accumulated for salutary effects of CO, BV, and/or BR in lung/vascular injury models, as well as in models of transplant-associated I/R injury. Thus, the exogenous application of HO end products may provide an alternative to pharmacologic or gene therapy approaches to harness the therapeutic potential of HO-1.

Key Words: bilirubin • carbon monoxide • heme oxygenase-1 • inflammation • ischemia/reperfusion

CLINICAL RELEVANCE This review discusses the use of heme metabolites as therapeutic agents for lung/vascular disease, with potential clinical applications.

 

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