PAF and Hypoxia-Induced Pulmonary Hypertension

描述(申请人提供)：本提案的总体目标是研究血小板激活因子(PAF)在慢性缺氧性肺动脉高压(PH)相关肺血管改变中的作用。我们先前已经证明，在低氧条件下，胎儿肺血管平滑肌(PVSMC)PAF合成和PAF受体(PAF-R)的表达都很高，而且这种表达在出生时就随着氧合而下调。我们的主要假设是，在胎儿的缺氧环境中，PAF在维持高肺血管舒张性方面起着生理作用，并可能促进血管的生长；然而，在慢性缺氧中，在宫内或新生儿期，PAF介导的信号过度导致PVSMC和外膜成纤维细胞(AF)增殖，血管重塑和异常血管收缩导致肺高压。本研究的具体目的是：1.研究PAF在新生小牛慢性缺氧性肺动脉高压和PAF受体敲除及过表达转基因小鼠中的作用。2.探讨低氧条件下PAF对肺血管平滑肌和外膜成纤维细胞的作用机制。具体地说，我们将确定PAF与其受体相互作用导致SMC收缩的信号转导途径；PAF在低氧条件下刺激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转分化的机制。这些实验将使我们能够了解PAF介导的慢性低氧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在慢性缺氧性PH发病机制中作用的细胞机制的理解。这应该使我们能够开发出更好的预防和治疗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.