Carbon monoxide: from silent killer to potential remedy

Abstract

EDITORIAL FOCUSCarbon monoxide: from silent killer to potential remedyNathalie Hill-Kapturczak, and Anupam AgarwalNathalie Hill-KapturczakSearch for more papers by this author, and Anupam AgarwalSearch for more papers by this authorPublished Online:01 Apr 2006https://doi.org/10.1152/ajprenal.00495.2005MoreSectionsPDF (39 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat All substances are poisonous, there is none which is not a poison. The right dose differentiates a poison from a remedy. —Paracelsusthoughts that come to mind when the words carbon monoxide (CO) are heard include accidental deaths from malfunctioning home appliances, suicides in closed garages, and assisted suicides (Jack Kevorkian, a.k.a. Dr. Death). In fact, the top 10 sites in a Google search for CO are all related to the toxic effects of this gas. CO is a colorless, tasteless, and odorless gas that, when inhaled, enters the bloodstream and replaces the oxygen on hemoglobin, forming carboxyhemoglobin. Increasing levels of carboxyhemoglobin can result in a wide range of symptoms from mild cognitive impairment including reduction in visual perception and driving performance to more severe effects like headache, weakness, gastrointestinal symptoms, and finally progressive confusion, collapse, and coma. The major exogenous source for CO is the incomplete burning of carbon from solid, liquid, and gaseous fuels. The United States National Ambient Air Quality Standards for CO levels in outdoor air are 9 parts/million (ppm) for 8 h and 35 ppm for 1-h exposure. However, no standards for indoor air CO levels have been agreed upon.Although the toxicity of CO has been extensively studied, it is now also being explored for its physiological effects and potential therapeutic benefits (9, 19). Since the realization that the poisonous gas, nitric oxide (NO), has a significant biological role in physiology and pathophysiology, CO, which is a structurally similar gas, has gained significant attention as a molecule with many analogous chemical and biological properties (19). Like NO, CO is produced endogenously during cellular metabolism, primarily from the degradation of heme by the heme oxygenase (HO) enzyme system, which comprises two main isoforms, an inducible enzyme, HO-1, and a constitutive one, HO-2 (10). HO-1 is activated in a wide range of injurious settings and serves as an adaptive and protective response (2, 8, 15, 16). The beneficial effects of HO-1 induction are mediated, in large part, through one or more of its reaction products including bile pigments and CO (8, 21). Endogenous CO formation has been measured in several biological systems, and humans have been shown to exhale ∼10 ml of CO/day (11).The intracellular mechanisms for the actions of CO are not completely understood. CO binds to the iron of heme proteins and affects several intracellular signaling pathways, including soluble guanylyl cyclase, mitogen-activated protein kinases (MAPK), particularly p38 MAPK, and the antioxidant enzyme manganese superoxide dismutase (3, 18, 26). CO has been shown to ameliorate inflammation, vascular dysfunction, and transplant rejection in several animal models through its vasodilatory, anti-inflammatory, antiapoptotic, and immunomodulatory properties (reviewed in Ref. 2222). Over the last decade, CO has become the subject of intense investigation and is emerging as a potential therapeutic molecule. The clinical use of CO, however, is not without controversy. One major criticism is that while CO administered as a gas is cytoprotective in both in vitro and in vivo cellular and tissue injury models, the concentrations of CO used can lead to hemoglobin saturation, tissue hypoxia, and injury (22, 27).The recent identification and characterization of CO-releasing molecules (CO-RMs) by Motterlini and colleagues (12) have initiated and will promote further progress in studies of the physiological properties of CO. Most CO-RMs are transition metal-containing carbonyls; however, more recently a boron-based CO-RM (CORM-A1) which does not contain a transition metal has been identified and releases CO at a slower rate compared with transition metal-containing CO-RMs (6, 13). CO-RMs are capable of carrying and delivering CO to biological systems and exert functional effects including blood vessel relaxation, lowering of blood pressure, protection against cardiac and renal ischemia-reperfusion injury, and suppression of endotoxin-induced inflammatory responses (5–7, 23, 28).In this issue of the American Journal of Physiology-Renal Physiology, Tayem and colleagues (25) have further explored the role of CO, released from a water-soluble, transition metal-containing carbonyl (CORM-3) (4), in cisplatin-mediated renal injury in vitro and in vivo. A major limitation to the anticancer effects of the chemotherapeutic agent cisplatin is its dose-dependent nephrotoxicity, which occurs in about one-third of patients receiving the drug. Previous work has demonstrated that chemical inhibition of HO enzyme activity or genetic deficiency of HO-1 worsens cisplatin-induced renal failure, suggesting that HO-1 has a protective role in this model (1, 24). As HO enzyme activity results in the release of CO and bile pigments, the use of CO-RMs allows for the contribution of CO to be more thoroughly investigated. In this work, LLC-PK1 cells exposed to cisplatin and CORM-3, but not biliverdin, displayed significantly less apoptosis, and this cytoprotective effect was dependent on activation of the cGMP pathway (25). Intraperitoneal administration of CORM-3 but not inactive CORM-3 (iCORM-3) attenuated both structural and functional indexes of renal injury in a rat model of cisplatin nephrotoxicity. CORM-3 treatment even in the presence of tin protoporphyrin, an inhibitor of HO enzyme activity, was able to partially rescue renal function in the cisplatin model (25).It is possible that a combination of CO with other HO reaction products may further enhance protection. For example, Nakao et al. 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Agarwal, Div. of Nephrology, ZRB 614, Univ. of Alabama at Birmingham, 703 19th St. South, Birmingham, AL 35294 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByDual gas sensor with innovative signal analysis based on neural networkSensors and Actuators B: Chemical, Vol. 373A Sensitive and Reliable Carbon Monoxide Monitor for Safety-Focused Applications in Coal Mine Using a 2.33-$\mu$ m Laser DiodeIEEE Sensors Journal, Vol. 20, No. 1Norborn-2-en-7-ones as physiologically-triggered carbon monoxide-releasing prodrugs1 January 2017 | Chemical Science, Vol. 8, No. 8Carbon monoxide alleviates lipopolysaccharide-induced oxidative stress injury through suppressing the expression of Fis1 in NR8383 cellsExperimental Cell Research, Vol. 349, No. 1Simvastatin Treatment Ameliorates Injury of Rat Testes Induced by Cadmium Toxicity28 April 2013 | Biological Trace Element Research, Vol. 153, No. 1-3Protective effects of captopril in diabetic rats exposed to ischemia/reperfusion renal injury7 September 2012 | Journal of Pharmacy and Pharmacology, Vol. 65, No. 2Plasma and Urinary Heme Oxygenase-1 in AKI22 March 2012 | Journal of the American Society of Nephrology, Vol. 23, No. 6Preconditioning with Hyperbaric Oxygen Induces Tolerance Against Renal Ischemia-Reperfusion Injury Via Increased Expression of Heme Oxygenase-1Journal of Surgical Research, Vol. 170, No. 2Hyperbaric Oxygen for Acute Carbon Monoxide Poisoning11 January 2010Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: a comprehensive review22 September 2007 | Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 376, No. 1-2Heme oxygenase-1 protects against radiocontrast-induced acute kidney injury by regulating anti-apoptotic proteinsKidney International, Vol. 72, No. 8 More from this issue > Volume 290Issue 4April 2006Pages F787-F788 Copyright & PermissionsCopyright © 2006 the American Physiological Societyhttps://doi.org/10.1152/ajprenal.00495.2005PubMed16527924History Published online 1 April 2006 Published in print 1 April 2006 Metrics