Sickle cell disease: role of reactive oxygen and nitrogen metabolites.
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.
Wood
Katherine C
KC
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
Granger
D Neil
DN
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
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