PROSTANOID BIOSYNTHESIS IN SYSTEMIC MASTOCYTOSIS

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The objective of the proposed research is to examine the biosynthesis of the mast cell mediator, prostaglandin D2, in patients with systemic mastocytosis, and to explore the potential for improvements in the treatment of this disorder. Prostaglandin D2 (PGD2) is the predominant prostaglandin synthesized by the mast cell and this vasodilator contributes to the attacks of hypotension/shock experienced by some patients with systemic mastocytosis. Inhibition of PGD2 biosynthesis with nonselective cyclooxygenase inhibitors (the nonsteroidal anti- inflammatory drugs) has been employed in the treatment of this disorder, but these drugs that block both cyclooxygenase-1 and cyclooxygenase-2 cause major gastrointestinal adverse effects. Either or both of the cyclooxygenase isoforms could be responsible for the biosynthesis of PGD2 in the mast cells of these patients. In the proposed studies, the contribution of and cyclooxygenase-2 to the biosynthesis of PGD2 will be examined, utilizing a selective COX-2 inhibitor, rofecoxib, as a pharmacologic probe for COX-2 dependent PGD2 production. This question also will be addressed by examination of the expression of COX- 1 and COX-2 in mast cells present in the bone marrow and skin of patients with systemic mastocytosis.