Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

Abstract

The heme oxygenase-1 (HO-1) enzyme system remains an attractive therapeutic target for the treatment of inflammatory conditions. HO-1, a cellular stress protein, serves a vital metabolic function as the rate-limiting step in the degradation of heme to generate carbon monoxide (CO), iron, and biliverdin-IXα (BV) which is converted to bilirubin-IXα (BR). HO-1 may function as a pleiotropic regulator of inflammatory signaling programs, through the generation of its biologically active end-products, namely CO and BV/BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of pro- or anti-inflammatory cytokines and mediators. HO-1/CO may also have immunomodulatory effects with respect to regulating the functions of antigen-presenting cells, dendritic cells, and regulatory T-cells. Therapeutic strategies to modulate HO-1 in disease include the application of natural inducing compounds, as well as gene therapy approaches for the targeted genetic overexpression or knockdown of HO-1. Several compounds have been used therapeutically to inhibit HO activity, including competitive inhibitors of the metalloporphyrin series, or non-competitive isoform-selective derivatives of imidazole-dioxolanes. The end-products of HO activity, BV/BR and CO may be used therapeutically as pharmacological treatments. CO may be applied by inhalation, or through the use of CO releasing molecules (CORMs). This review will discuss HO-1 as a therapeutic target in diseases involving inflammation, including lung and vascular injury, sepsis, ischemia/reperfusion injury and transplant rejection.