EICOSANOIDS IN SICKLE-CELL DISEASE - POTENTIAL RELEVANCE OF 12(S)-HYDROXY-5,8,10,14-EICOSATETRAENOIC ACID TO THE PATHOPHYSIOLOGY OF VASOOCCLUSION

The monohydroxyeicosanoid 12(S)-hydroxy-5,8,10,14-elcosatetraenoic aci d (12-HETE), which is derived from oxygenation of arachidonic acid by la-lipoxygenase, is one of the major metabolites in platelets. In a re cent study, we have showed that this eicosanoid stimulated basal sickl e-red-cell-endothelial-cell adhesion. To understand the pathophysiolog ic significance of 12-HETE, we measured the levels of this eicosanoid in plasma and urine from children with sickle cell disease. We found t hat as compared with controls, plasma 12-HETE levels are increased in patients with sickle-cell disease in the steady state, and are increas ed further during vaso-occlusive crises, Urinary 12-HETE levels were a lso increased during the steady state. We also assessed plasma levels of soluble P-selectin (another potential marker for platelet activatio n), and found changes in the levels of this marker similar to those se en with plasma 12-HETE, In additional studies, we found that 12-HETE e nhanced hypoxia-induced sickle-red-cell-endothelial adherence, and tha t this effect was mediated by potentiation of agonist-induced upregula tion of the expression of the mRNA for vascular cell adhesion molecule -1 (VCAM-1) in endothelial cells. Because 12-HETE appears to enhance b oth basal and agonist-induced sickle-red-cell adhesion, this metabolit e could potentially play a role in the pathogenesis of the vaso-occlus ive crisis (VOC) in sickle-cell disease.