EICOSANOIDS AND PULMONARY VASCULAR TONE

描述（申请人的摘要）：近年来， 血管内皮合成和释放的各种因子 对调节血管张力的作用已经变得很明显。 在 肺血管，这些研究人员已经确定了一个 内皮依赖性收缩因子作为血管收缩剂血栓素 A2. 有一些事件，其中增加的合成 血栓素A2与肺部疾病相关，包括肺 高血压和猝死。 因此， 建议的研究是调查花生四烯酸是 通过肺血管代谢为血栓素A2， 血栓素A2是一种重要的介体，参与调节 正常和病理生理状态下的肺血管张力。 具体地，已知花生四烯酸和乙酰甲胆碱诱导的 肺动脉的收缩由血栓素A2介导， 去除内皮层消除了收缩。 然而， 从肺动脉分离的内皮细胞不能合成 血栓素A2。 具体目标1描述的实验将研究 肺血管中血栓素A2合成需要 内皮细胞与贴壁细胞之间的相互作用。 可能 贴壁细胞的候选物包括血小板、多形核细胞 白细胞或单核细胞。 研究表明，血栓素A2诱导的 血小板聚集和血管平滑肌血管收缩是由 通过激活膜结合受体。 研究的一个局限性是， 血栓素A2在肺部疾病中的作用是不能 区分血小板和血管平滑肌的贡献 肌肉受体对观察到的血流动力学反应，因为可用的 不幸的是，血栓烷受体拮抗剂是非选择性的， 血小板受体和血管受体。 调查人员发现 一组缺乏血管，但不缺乏血小板的兔子， 血栓素A2受体。 具体目标2描述的实验将使用 这些兔子来研究血栓素A2及其 血管受体在肺血管调节中起重要作用 语气 具体来说，他们将调查年龄和性别的影响 对血栓素激动剂和血栓素A2的血管反应性 受体密度，表征受体数量的差异， 从应答者培养的血管细胞中的功能应答， 无反应肺动脉，并评估血管的作用， 血栓素A2受体在肺栓塞模型中的作用。

DESCRIPTION (Applicant's abstract): In recent years, the importance of various factors synthesized and released from the blood vessel endothelium that contribute to the regulation of vascular tone has become apparent. In pulmonary vessels, these investigators have identified an endothelium-dependent contracting factor as the vasoconstrictor thromboxane A2. There are a number of incidences where an increased synthesis of thromboxane A2 is associated with pulmonary disease, including pulmonary hypertension and sudden death. Therefore, the long term objective of the proposed studies is to investigate the hypothesis that arachidonic acid is metabolized by pulmonary blood vessels to thromboxane A2 and that thromboxane A2 is an important mediator involved in the regulation of pulmonary vascular tone under both normal and pathophysiological states. Specifically, it is known that arachidonic acid and methacholine-induced contractions of pulmonary arteries are mediated by thromboxane A2 and removal of the endothelial layer abolishes the contractions. Yet, endothelial cells isolated from pulmonary arteries do not synthesize thromboxane A2. Experiments described by specific aim 1 will investigate the hypothesis that thromboxane A2 synthesis in pulmonary vessels requires the interaction between the endothelial cells and adherent cells. Possible candidates for the adherent cells include platelets, polymorphonuclear leukocytes or monocytes. Studies have shown that thromboxane A2-induced platelet aggregation and vascular smooth muscle vasoconstriction is mediated via activation of a membrane-bound receptor. One limitation to studying the role of thromboxane A2 in pulmonary disease is the inability to differentiate the contribution of the platelet and the vascular smooth muscle receptor to the observed hemodynamic responses because the available thromboxane receptor antagonists are unfortunately non-selective and block both the platelet and vascular receptors. The investigators have identified a subset of rabbits that are deficient in vascular, but not platelet, thromboxane A2 receptors. Experiments described by specific aim 2 will use these rabbits to investigate the hypothesis that thromboxane A2 and its vascular receptor are important to the regulation of pulmonary vascular tone. Specifically, they will investigate the influence of age and gender on the vascular responsiveness to thromboxane agonist and thromboxane A2 receptor density, characterize the differences in receptor number and functional responses in vascular cells cultured from responder and nonresponder pulmonary arteries and assess the role of the vascular thromboxane A2 receptor in a model of pulmonary embolism.