PAF and Hypoxia-Induced Pulmonary Hypertension

描述（由申请人提供）：本提案的总体目标是研究血小板活化因子（PAF）在慢性缺氧引起的肺动脉高压（PH）相关的肺血管变化中的作用。我们之前的研究表明，在缺氧条件下，胎儿肺血管平滑肌（PVSMC）中，PAF合成和PAF受体（PAF- r）表达高，并且在出生时随着氧合而下调。我们的主要假设是，在胎儿缺氧环境下，PAF在维持高肺血管舒缩张力方面发挥生理作用，并可能有助于血管生长；然而，在慢性缺氧时，在子宫内或新生儿时期，paf介导的信号过多导致PVSMC和外内膜成纤维细胞（AF）增生和血管重塑和血管异常收缩导致肺动脉高压。具体目标是：1。证明PAF在新生牛犊慢性缺氧诱导的肺动脉高压和PAF受体敲除和过表达转基因小鼠中的作用。2. 探讨缺氧条件下PAF在肺血管平滑肌和外膜成纤维细胞中的作用机制。具体来说，我们将确定缺氧时PAF与其受体相互作用导致SMC收缩的信号转导途径；缺氧条件下PAF刺激PVSMC和AF增殖的机制以及PAF诱导成纤维细胞向肌成纤维细胞反分化的机制。这些实验将使我们了解慢性缺氧时paf介导的肺血管重构和血管收缩的机制。我们的研究结果将增加我们对PAF参与慢性缺氧诱导PH发病机制的细胞机制的理解，这将使我们能够开发更好的预防和治疗PH的方法。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to investigate the role of platelet activating factor (PAF) in the lung vascular changes associated with chronic hypoxia-induced pulmonary hypertension (PH). We have previously shown that in fetal pulmonary vascular smooth muscle (PVSMC), under hypoxic conditions, PAF synthesis and PAF receptor (PAF-R) expression are high, and that this is down regulated at birth with oxygenation. Our main hypothesis is that in the hypoxic environment of the fetus, PAF plays a physiological role in maintaining high pulmonary vasomotor tone and may contribute to vascular growth; however, in chronic hypoxia, in utero or in the newborn period, there is excessive PAF-mediated signaling leading to PVSMC and adventitial fibroblast (AF) hyperplasia and vascular remodeling and abnormal vasoconstriction resulting in pulmonary hypertension. The specific aims are: 1. To demonstrate a role for PAF in chronic hypoxia-induced pulmonary hypertension in neonatal calves and in PAF-receptor knock-out and over-expressing transgenic mice. 2. To investigate the mechanisms by which PAF, in the presence of hypoxia, mediates its effects in pulmonary vascular smooth muscle and adventitial fibroblasts. Specifically, we will determine the signal transduction pathway by which PAF interactions with its receptor in hypoxia leads to SMC contraction; the mechanisms by which PAF stimulates PVSMC and AF proliferation in hypoxia and the mechanism of PAF-induced trans-differentiation of fibroblasts to myo-fibroblasts. These experiments will enable us to understand the mechanisms of PAF-mediated pulmonary vascular remodeling and vaso-constriction in chronic hypoxia. Results from our studies should increase our understanding of the cellular mechanisms by which PAF contributes to the pathogenesis of chronic hypoxia-induced PH. This should enable us to develop better methods of prevention and treatment of PH.