Acute chest syndrome (ACS) is common in patients with sickle cell disease and has a decreasing incidence by increasing age. Episodes of ACS may result in pulmonary fibrosis and increased mortality in both children and adults. Clinical symptoms and laboratory markers of inflammation are found in patients with acute chest syndrome in Sickle Cell Disease, implicating a primary or secondary role in the pathogenesis of sickle-erythrocyte dependent disruption of normal pulmonary function. Accordingly, we hypothesize that sickle erythrocytes stimulate the endothelium in the pulmonary microvasculature to express adhesion receptors and cytokines, which in turn, activate leukocytes to release mediators of inflammation that cause damage to the lungs and produce acute chest syndrome. Moreover, in children, the acute chest syndrome may be precipitated or augmented by viral or bacterial infections, classic activators of leukocytes within the inflammatory response of the host. Recent research demonstrates the critical role of the endothelium in leukocyte-vessel wall interactions during initial phases of the inflammatory response. Interference with leukocyte-vessel wall interactions in clinical and laboratory studies has been shown to be beneficial to the host leading to reduction of tissue destruction and clinical improvement. In this study, we propose to test the leukocyte-vessel wall interaction hypothesis by assessment of clinical and laboratory parameters and response to early treatment with corticosteroids. Specifically, we propose to a) determine the prevalence of infections in children with ACS, b) document the in vivo activation of endothelial cells and neutrophils, c) determine the ability of sickle erythrocytes to activate endothelial adhesion molecules (ELAM-1, ICAM-1, and VCAM-1) in an in vitro model of the venular vessel wall, d) measure the ability pathologic endothelial- leukocyte interactions to induce structural and functional damage, and e) to test in a randomized, controlled study enrolling 24 patients per year the effect of acute corticosteroid administration on protection of pulmonary function, normalization of leukocyte-vessel wall interaction an decrease in morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Comprehensive Center (P60)
Project #
5P60HL048482-04
Application #
5213953
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
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