title: Sickle cell disease: role of reactive oxygen and nitrogen metabolites.
abstract: 1. Sickle cell disease (SCD) is an inherited disorder of haemoglobin synthesis that is associated with significant morbidity and mortality due to sequelae of episodic vaso-occlusive events: pain crises and multiorgan damage. The microvascular responses to the initiation, progression and resolution of vaso-occlusive events are consistent with an inflammatory phenotype as suggested by activation of multiple cell types, an oxidatively stressed environment and endothelial cell dysfunction. 2. Decreased anti-oxidant defences in SCD patients and mice are accompanied by activation of enzymatic (NADPH oxidase, xanthine oxidase) and non-enzymatic (sickle haemoglobin auto-oxidation) sources of reactive oxygen species. The resultant oxidative stress leads to dysfunction/activation of arteriolar and venular endothelial cells, resulting in impaired vasomotor function and blood cell-endothelial cell adhesion. 3. Changes in substrate and cofactor availability for endothelial cell nitric oxide synthase may underlie reactive oxygen- and nitrogen-induced events that contribute to SCD-induced vasculopathy. 4. The emerging role of reactive oxygen and nitrogen species in the pathogenesis of SCD provides a platform for the development of novel agents to treat this painful and lethal disease.
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Wood
authors.forename: D Neil
authors.initials: DN
authors.lastname: Granger
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D004903:Erythrocyte Aggregation; D006451:Hemoglobin, Sickle / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D007502:Iron Chelating Agents / Q000627:therapeutic use; D036904:Leukocyte Rolling; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000627:therapeutic use; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010973:Platelet Adhesiveness; D026361:Reactive Nitrogen Species / Q000097:blood / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000097:blood / Q000378:metabolism*; D014664:Vasodilation; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D000986:Antisickling Agents; D004791:Enzyme Inhibitors; D006451:Hemoglobin, Sickle; D007502:Iron Chelating Agents; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D014969:Xanthine Oxidase; D019255:NADPH Oxidases; D006918:Hydroxyurea