Targeting heme oxygenase 1 and carbon monoxide for therapeutic modulation of inflammation.
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 IXa (BV) the latter which is converted to bilirubin IXa (BR) HO 1 may function as a pleiotropic regulator of inflammatory signaling programs through the generation of its biologically active end products, namely CO, BV and BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of proinflammatory or anti inflammatory cytokines and mediators. HO 1 and 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 and 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 noncompetitive isoform selective derivatives of imidazole dioxolanes. The end products of HO activity, CO, BV and BR may be used therapeutically as pharmacologic treatments. CO may be applied by inhalation or through the use of CO releasing molecules. 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.
Translational research the journal of laboratory and clinical medicine