PULMONARY ENDOTHELIAL FUNCTION DURING CHRONIC HYPOXIA

慢性缺氧期间的肺内皮功能

基本信息

批准号：
6537315
负责人：
BENJIMEN R WALKER
金额：
$ 26.27万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2004-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6537315
关键词：
RNase protection assay endothelin enzyme activity enzyme induction /repression laboratory rat lung ischemia /hypoxia mechanical stress monocrotaline nitric oxide nitric oxide synthase pulmonary circulation pulmonary hypertension respiratory pharmacology vascular endothelium vasoconstriction

项目摘要

DESCRIPTION (Verbatim from the Applicant's Abstract): Recent studies suggest that chronic exposure to hypoxia causes upregulation of both endothelial and inducible nitric oxide synthase (eNOS and iNOS, respectively) within the lung. Responses to endothelium-derived NO (EDNO)-dependent dilators are enhanced the arterial vasculature of the lung under hypoxic conditions. However, the mechanisms by which eNOS and iNOS gene expression are increased in hypoxia-induced pulmonary hypertension are unclear. The two most likely possibilities are: 1) a direct effect of hypoxia on gene expression; or 2) an effect of altered mechanical forces secondary to pulmonary hypertension. In regulation of pulmonary NO and endothelin biosynthesis under these clinically relevant conditions. The specific aims are: Specific Aim 1 - Determine whether hypoxia per se or pulmonary hypertension is responsible for altered vasoreactivity and upregulation of eNOS and iNOS in lungs from chronically hypoxic rats; Specific Aim 2 - Determine whether pulmonary hypertension in the absence of hypoxia alters pulmonary vascular reactivity and expression of eNOS and iNOS; Specific Aim 3 - Determine the roles of increased shear stress, hypoxia and endothelin on eNOS and iNOS expression in cultured cells and in isolated arteries; and Specific Aim 4 - Examine the potential in vivo interactions between the endothelin and NOS systems in hypoxia-induced pulmonary hypertension. The proposed experiments utilize a variety of in vivo and in vitro approaches to examine questions central to the regulation of the pulmonary circulation under clinically relevant conditions.

描述（逐字摘自申请人的摘要）：最近的研究表明长期暴露于缺氧会导致内皮细胞和肺内的诱导型一氧化氮合酶（分别为 eNOS 和 iNOS）。对内皮源性 NO (EDNO) 依赖性扩张剂的反应增强缺氧条件下肺动脉血管系统。然而， eNOS 和 iNOS 基因表达增加的机制缺氧引起的肺动脉高压尚不清楚。最有可能的两个可能性有：1）缺氧对基因表达的直接影响；或 2) 一个继发于肺动脉高压的机械力改变的影响。在临床上这些情况下肺NO和内皮素生物合成的调节相关条件。具体目标是：具体目标 1 - 确定是否缺氧本身或肺动脉高压是造成改变的原因慢性肺内 eNOS 和 iNOS 的血管反应性和上调缺氧大鼠；具体目标 2 - 确定肺动脉高压是否存在缺乏缺氧会改变肺血管反应性和 eNOS 的表达和诱导型一氧化氮合酶（iNOS）；具体目标 3 - 确定剪切应力增加的作用，缺氧和内皮素对培养细胞和体内 eNOS 和 iNOS 表达的影响孤立的动脉；和具体目标 4 - 检查体内潜力缺氧诱导的内皮素和 NOS 系统之间的相互作用肺动脉高压。所提出的实验利用了多种体内和体外方法来检查对监管至关重要的问题临床相关条件下的肺循环。