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

  • Stefan W. Ryter
    Correspondence
    Reprint requests: Stefan W. Ryter, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical Center, 525 East 68th Street, Room M-522, Box 130, New York, NY 10065
    Affiliations
    Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY
    Search for articles by this author
  • Augustine M.K. Choi
    Affiliations
    Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY
    Search for articles by this author
      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), the latter 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, 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.

      Abbreviations:

      ALI (acute lung injury), APCs (antigen-presenting cells), ARE (antioxidant responsive element), Bach1 (Broad complex–Tramtrack–Bric-a-brac (BNB) and Cap'n'collar (CNC) homolog 1), BAL (bronchoalveolar lavage), BR (bilirubin-IXα), BV (biliverdin-IXα), BVR (biliverdin reductase), CNC (Cap'n'collar), CO (carbon monoxide), CO-Hb (carboxyhemoglobin), COPD (chronic obstructive pulmonary disease), CORM (CO-releasing molecule), CPR (cytochrome p-450 reductase), DCs (dendritic cells), DMF (dimethyl fumarate), EGR-1 (early growth response protein 1), ERK1/2 (extracellular regulated protein kinase 1/2), FoxP3 (forkhead box P3), HO (heme oxygenase), HFD (high-fat diet), HO-1 (heme oxygenase-1), HO-2 (heme oxygenase-2), HMGB1 (high-mobility group box 1), HSF-1 (heat shock factor 1), IFN-β (interferon beta), IL (interleukin), iNOS (inducible nitric oxide synthase), I/R (ischemia-reperfusion), JNK (c-Jun NH2-terminal kinase), Keap1 (kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein), LPS (lipopolysaccharide), MAPK (mitogen-activated protein kinase), miR (microRNA), MV (mechanical ventilation), NADH (nicotinamide adenine dinucleotide, reduced form), NADPH (nicotinamide adenine dinucleotide phosphate, reduced form), NLRP3 (NOD-, leucine rich region- and pyrin domain-containing 3), Nrf2 (nuclear factor erythroid 2–related factor 2), p38 MAPK (p38 mitogen-activated protein kinase), PI3K/Akt (phosphatidylinositol-3-kinase/Akt), PhotoCORMs (photoactivatable carbon monoxide-releasing molecules), ROS (reactive oxygen species), SCD (sickle cell disease), SMC (smooth muscle cells), SNP (small nucleotide polymorphism), SnPPIX (tin protoporphyrin IX), SPM (specialized proresolving mediators), StRE (stress-responsive element), TLR4 (toll-like receptor 4), Treg (regulatory T cells), VILI (ventilator-induced lung injury)
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