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To review the role of endothelial dysfunction and nitric oxide metabolism in the pathogenesis of the acute chest syndrome.A thorough literature search of PubMed for publications relevant to acute chest syndrome and nitric oxide metabolism in sickle cell disease was performed using search terms that included acute chest syndrome, sickle cell disease, nitric oxide metabolism, arginine, nitrite, nitrate, exhaled nitric oxide, nitric oxide synthase, and oxidant injury. We identified randomized controlled trials, case reports, editorials, and review articles from English-language and non-English-language studies of adult, pediatric, animal, and human subjects that describe the pathophysiology of acute chest syndrome, the biology of nitric oxide relevant to the pathophysiology of sickle cell disease, and the evidence for the role of endothelial dysfunction and abnormal nitric oxide metabolism in acute chest syndrome. We identified and reviewed 350 publications by the initial search and subsequent bibliography review. The articles most pertinent to the topic of this article were selected to support the discussion.Acute chest syndrome is the leading cause of acute respiratory system dysfunction and a leading cause of morbidity and mortality among patients with sickle cell disease. Evidence is available to support decreased nitric oxide production, increased nitric oxide consumption, and abnormal metabolism of nitric oxide in patients with acute chest syndrome. Moreover, substrate availability is disturbed, and alternate pathways for substrate and nitric oxide metabolism exist.Abnormalities of nitric oxide metabolism are prevalent during acute illness and baseline health in patients with sickle cell disease. Further investigation is needed to understand the clinical significance of aberrant nitric oxide metabolism as well as the potential for therapeutic manipulation of the arginine-nitric oxide pathway in patients with sickle cell disease.