LIPID MODULATORS OF PULMONARY VASCULAR TONE

虽然20-HETE在孕兔肺中的形成已被描述， 20多年前，细胞色素产物没有生理作用， 建立了肺系统P450 4A酶系。 我们 最近描述了一种剂量依赖性、环氧合酶依赖性 20-HETE对离体人肺动脉的血管舒张作用。 我们 还鉴定了免疫特异性蛋白质和20-HETE合成， 花生四烯酸在患者的整个肺微粒体中， 20-HETE是人肺的内源性产物。 我们的目标 实验的目的是检查细胞来源和机制， 在使用大鼠肺模型的20-HETE诱导的血管舒张的基础上。 我们 初步数据显示，20-HETE增加，cP 450 4A抑制剂 降低大鼠肺动脉钾通道开放概率 血管平滑肌细胞（PA VSM）。我们推测， 20-HETE的可用性可能有助于急性缺氧诱导 缺氧抑制20-HETE合成引起肺血管收缩 并证明用17-ODYA抑制cP 450 4A可增强 离体灌流肺缺氧性肺血管收缩反应。 该补助金的具体目标是（1）确定蜂窝 20-HETE形成的来源和环氧合酶的鉴别 肺组织中20-HETE的代谢产物（2），以进一步检查 环氧合酶依赖性20-HETE诱导 离体肺动脉的血管舒张（3），以检查 cP 450 4A在急性缺氧性血管收缩反应中的作用 离体灌流肺和（4）研究离子机制， 在分离的PA VSM中，20-HETE诱导的血管舒张的基础。 这些 实验应提供有关来源的重要信息， 细胞/离子机制介导20-HETE诱导的变化， 孤立的肺血管直径，并定位我们寻找 cP 450 4A产品的生理或病理生理条件 可能改变肺血管张力。

Although formation of 20-HETE in pregnant rabbit lungs was described over 20 years ago, no physiologic role for products of the cytochrome P450 4A enzyme system in the pulmonary system has been established. We recently described a dose dependent, cyclooxygenase dependent vasodilator action of 20-HETE on isolated human pulmonary arteries. We also identified immunospecific proteins and synthesis of 20-HETE from arachidonic acid in whole lung microsomes of patients, demonstrating that 20-HETE is an endogenous product of human lungs. The goal of our experiments is to examine the cellular sources and mechanisms which underlie 20-HETE induced vasodilation using a rat lung model. Our preliminary data show that 20-HETE increases and cP450 4A inhibitors decrease the open probability of K+ channels in rat pulmonary artery vascular smooth muscle cells (PA VSM). We speculate that reduced availability of 20-HETE may contribute to acute hypoxia induced pulmonary vasoconstriction in that hypoxia inhibits 20-HETE synthesis and demonstrate that inhibition of cP450 4A with 17-ODYA augments the hypoxic pulmonary vasoconstrictive response in isolated perfused lungs. The specific aims of this grant are (1) to determine the cellular source(s) of 20-HETE formation and the identity of the cyclooxygenase metabolite of 20-HETE in lung tissue (2) to further examine the mechanisms behind the cyclooxygenase dependent 20-HETE induced vasodilation of isolated pulmonary arteries (3) to examine the contribution of cP450 4A to acute hypoxic vasoconstrictive responses of isolated perfused lungs and (4) to study the ionic mechanisms which underlie 20-HETE induced vasodilation in isolated PA VSM. These experiments should provide important information about the sources and cellular/ionic mechanisms which mediate 20-HETE induced changes in isolated pulmonary vessel diameter, and position us to look for physiologic or pathophysiologic conditions in which cP450 4A products may alter pulmonary vascular tone.