Showing papers by "Leo E. Otterbein published in 2004"

Carbon monoxide in biology and medicine

Abstract: Carbon monoxide (CO), a product of organic oxidation processes, arises in vivo during cellular metabolism, most notably heme degradation. CO binds to the heme iron of most hemoproteins. Tissue hypoxia following hemoglobin saturation represents a principle cause of CO-induced mortality in higher organisms, though cellular targets cannot be excluded. Despite extreme toxicity at high concentrations, low concentrations of CO can confer cytoprotection during ischemia/reperfusion or inflammation-induced tissue injury. Likewise, heme oxygenase, an enzyme that produces CO, biliverdin and iron, as well as a secondary increase in ferritin synthesis, from the oxidation of heme, can confer protection in vivo and in vitro. CO has been shown to affect several intracellular signaling pathways, including guanylate cyclase, which generates guanosine 3':5' cyclic monophosphate and the mitogen-activated protein kinases (MAPK). Such pathways mediate, in part, the known vasoregulatory, anti-inflammatory, anti-apoptotic and anti-proliferative effects of this gas. Exogenous CO delivered at low concentrations is showing therapeutic potential as an anti-inflammatory agent and as such can modulate numerous pathophysiological states. This review will delve into the biological significance and medical applications of this gas molecule.

Heme oxygenase-1-derived carbon monoxide protects hearts from transplant associated ischemia reperfusion injury

Abstract: Heme oxygenase-1 (HO-1) degrades heme into iron, biliverdin, and carbon monoxide (CO). HO-1 expression can be used therapeutically to ameliorate undesirable consequences of ischemia reperfusion injury (IRI), but the mechanism by which this occurs, remains to be established. Rat hearts, exposed to a prolonged period (24 h) of cold (4 degrees C) ischemia, failed to function upon transplantation into syngeneic recipients. Induction of HO-1 expression by administration of cobalt protoporphyrin IX (CoPPIX) to the graft donor restored graft function. Inhibition of HO-1 enzymatic activity, by administration of zinc protoporphyrin (ZnPPIX) at the time of transplantation, reversed the protective effect of HO-1. Exposure of the graft donor as well as the graft (during ischemia) to exogenous CO mimicked the protective effect of HO-1. This was associated with a significant reduction in the number of cells undergoing apoptosis in the graft with no apparent decrease of intravascular fibrin polymerization, platelet aggregation, or P-selectin expression. In conclusion, HO-1-derived CO prevents IRI associated with cardiac transplantation based on its antiapoptotic action. The observation that exposure of the donor and the graft to CO is sufficient to afford this protective effect should have important clinical implications in terms of preventing IRI associated with heart transplantation in humans.

Protection of transplant-induced renal ischemia-reperfusion injury with carbon monoxide

Abstract: Carbon monoxide (CO), a product of heme metabolism by heme oxygenases, is known to impart protection against oxidative stress. We hypothesized that CO would protect ischemia-reperfusion (I/R) injur...

Carbon monoxide protection against endotoxic shock involves reciprocal effects on iNOS in the lung and liver

Abstract: Carbon monoxide (CO) has recently emerged as having potent cytoprotective properties; the mechanisms underlying these effects, however, are just beginning to be elucidated. In a rat model of lipopolysaccharide (LPS)-induced multiorgan failure, we demonstrate that exposure to a low concentration of CO for only 1 h imparts a potent defense against lethal endotoxemia and effectively abrogates the inflammatory response. Exposure to CO leads to long-term survival of >80% of animals vs. 20% in controls. In the lung, CO suppressed LPS-induced lung alveolitis and associated edema formation, while in the liver, it reduced expression of serum alanine aminotransferase, a marker of liver injury. This protection appears to be based in part on different mechanisms in the lung and liver in that CO had reciprocal effects on LPS-induced expression of iNOS and NO production, important mediators in the response to LPS. CO prevented the up-regulation of iNOS and NO in the lung while augmenting expression of iNOS and NO in the liver. Studies of primary lung macrophages and hepatocytes in vitro revealed a similar effect; CO inhibited LPS-induced cytokine production in lung macrophages while reducing LPS-induced iNOS expression and nitrite accumulation and protected hepatocytes from apoptosis while augmenting iNOS expression. Although it is unclear to which extent these changes in iNOS contribute to the cytoprotection conferred by CO, it is fascinating that in each organ CO influences iNOS in a manner known to be protective in that organ: NO is therapeutic in the liver while it is damaging in the lung.

Carbon Monoxide Inhibits T Lymphocyte Proliferation via Caspase-Dependent Pathway

Abstract: T lymphocyte activation and proliferation is involved in many pathological processes. We have recently shown that carbon monoxide (CO), an enzymatic product of heme oxyenase-1 (HO-1), confers potent antiproliferative effects in airway and vascular smooth muscle cells. The purpose of this study was to determine whether CO can inhibit T lymphocyte proliferation and then to determine the mechanism by which CO can modulate T lymphocyte proliferation. In the presence of 250 parts per million CO, CD3-activated T lymphocyte proliferation was, remarkably, inhibited by 80% when compared with controls. We observed that the antiproliferative effect of CO in T lymphocytes was independent of the mitogen-activated protein kinase or cGMP signaling pathways, unlike what we demonstrated previously in smooth muscle cells. We demonstrate that CO inhibited caspase-3 and caspase-8 expression and activity, and caspase inhibition with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK pan-caspase inhibitor) blocked T lymphocyte proliferation. Furthermore, in caspase-8-deficient lymphocytes, the antiproliferative effect of CO was markedly attenuated, further supporting the involvement of caspase-8 in the antiproliferative effects of CO. CO also increased the protein level of p21Cip1, and CO-mediated inhibition of caspase activity is partially regulated by p21Cip1. Taken together, these data suggest that CO confers potent antiproliferative effects in CD3-activated T lymphocytes and that these antiproliferative effects in T lymphocytes are mediated by p21Cip1-dependent caspase activity, in particular caspase-8, independent of cGMP and mitogen-activated protein kinase signaling pathways.

Carbon monoxide improves cardiac energetics and safeguards the heart during reperfusion after cardiopulmonary bypass in pigs

Abstract: Ischemia-reperfusion injury, a clinical problem during cardiac surgery, involves worsened adenosine trisphosphate (ATP) generation and damage to the heart. We studied carbon monoxide (CO) pretreatment, proven valuable in rodents but not previously tested in large animals, for its effects on pig hearts subjected to cardiopulmonary bypass with cardioplegic arrest. Hearts of CO-treated pigs showed significantly higher ATP and phosphocreatine levels, less interstitial edema, and apoptosis of cardiomyocytes and required fewer defibrillations after bypass. We conclude that treatment with CO improves the energy status, prevents edema formation and apoptosis, and facilitates recovery in a clinically relevant model of cardiopulmonary bypass surgery.

'Til cell death do us part: nitric oxide and mechanisms of hepatotoxicity

Abstract: Like many juggernauts in biology, the elusive nature of nitric oxide (NO) sprints through the fields, sometimes the savior, at other times the scimitar. In the liver, which is the metabolic center of the organism, hepatocytes and immune cells trade blows using the reactive diatomic molecule NO to induce cellular damage under toxic conditions. In response, hepatocytes can utilize several mechanisms of NO to their protective advantage by prohibiting the activation of programmed cell death, a.k.a. apoptosis. The balance of these effects in this reactive milieu set the stage for the homeostatic response to cellular injury that determines whether hepatocytes will live, die, or regenerate. Insights that we and others have gained from the liver under pathologic conditions of stress can be applied to the understanding of cellular death mechanisms in other organs and tissues.

Carbon Monoxide and Signal Transduction Pathways

Abstract: Carbon monoxide (CO) is emerging as an important signaling molecule that exerts a myriad of biological effects that are only recently being uncovered. CO is a diatomic gas that is generated predominantly from heme degradation by the enzyme heme oxygenase. Traditionally considered a biological “waste product” of heme metabolism and, at high doses, lethal, CO clearly has diverse functions including the modulation of neural signals, inflammation, cell proliferation, cell death, and smooth muscle contractility. Interestingly, at concentrations well below those that would otherwise create toxic effects, CO has beneficial effects in various models of injury and inflammation. The precise mechanisms of these CO-mediated effects are yet unknown but are becoming the focus of intense investigations. This chapter reviews the known signal transduction pathways of CO with a special emphasis on the roles of guanylate cyclase, the mitogen-activated protein kinases, and nuclear factor-κB.