title: The role of carbon monoxide and heme oxygenase in the prevention of sickle cell disease vaso-occlusive crises.
abstract: Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta-globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso-occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo-enzymes as well as key modulating genes that in sum, result in significant anti-inflammatory, anti-oxidant and anti-apoptotic effects as well as vasodilation and anti-adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti-polymerization HbS agent. In addition, considerable scientific data in the non-SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.
authors.affiliation: Hillhurst Biopharmaceuticals, Inc, 2029 Verdugo Blvd., #125, Montrose, CA, 91020, USA.
authors.forename: Edward
authors.identifier: http://orcid.org/0000-0001-5904-265X
authors.initials: E
authors.lastname: Gomperts
authors.affiliation: University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN, 55455, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Belcher
authors.affiliation: Harvard Medical School; Beth Israel Deaconess Medical Center, 3 Blackfan Circle Center for Life Sciences, #630, Boston, MA, 02115, USA.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.affiliation: Children's Hospital Los Angeles; University of Southern California, 4650 Sunset Boulevard MS #54 Los Angeles, CA, 90027, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Coates
authors.affiliation: Children's Hospital Los Angeles; University of Southern California, 4650 Sunset Boulevard MS #54 Los Angeles, CA, 90027, USA.
authors.forename: John
authors.initials: J
authors.lastname: Wood
authors.affiliation: Hillhurst Biopharmaceuticals, Inc, 2029 Verdugo Blvd., #125, Montrose, CA, 91020, USA.
authors.forename: Brett E
authors.initials: BE
authors.lastname: Skolnick
authors.affiliation: Hillhurst Biopharmaceuticals, Inc, 2029 Verdugo Blvd., #125, Montrose, CA, 91020, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Levy
authors.affiliation: University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN, 55455, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Vercellotti
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000378:metabolism*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D006419:Heme Oxygenase (Decyclizing) / Q000097:blood / Q000378:metabolism*; D006454:Hemoglobins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction; D016896:Treatment Outcome; D014652:Vascular Diseases / Q000209:etiology* / Q000517:prevention & control*
chemical_list: D006454:Hemoglobins; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing)