PROSTANOID BIOSYNTHESIS IN SYSTEMIC MASTOCYTOSIS

拟议的研究的目的是检查肥大细胞介质，前列腺素D2，在系统性肥大细胞增多症患者的生物合成，并探讨改善这种疾病的治疗的潜力。前列腺素D2（PGD 2）是肥大细胞合成的主要前列腺素，这种血管扩张剂导致一些全身性肥大细胞增多症患者发生低血压/休克。用非选择性环氧合酶抑制剂（非甾体抗炎药）抑制PGD 2生物合成已用于治疗这种疾病，但这些阻断环氧合酶-1和环氧合酶-2的药物引起主要的胃肠道不良反应。一种或两种环氧合酶亚型可能负责这些患者肥大细胞中PGD 2的生物合成。在所提出的研究中，将利用选择性考克斯-2抑制剂罗非昔布作为考克斯-2依赖性PGD 2产生的药理学探针，检查和环氧合酶-2对PGD 2生物合成的贡献。这个问题也将通过检查系统性肥大细胞增多症患者骨髓和皮肤中肥大细胞中考克斯- 1和考克斯-2的表达来解决。

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.