Regulation of lung epithelial injury by plasminogen activator inhibitor-1

纤溶酶原激活剂抑制剂-1对肺上皮损伤的调节

基本信息

批准号：
7990804
负责人：
Sreerama Shetty
金额：
$ 17.63万
依托单位：
UNIVERSITY OF TEXAS HLTH CTR AT TYLER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7990804
关键词：
Acute Address Affect Alveolar Apoptosis Area Binding Blood Clot Blood coagulation Cause of Death Cell Death Cells Characteristics Chronic Obstructive Airway Disease Coagulation Process Data Development Epithelial Epithelial Cells Epithelium Fibrin Fibrinolysis Fibrosis Human In Vitro Inflammation Injury Intervention Knowledge Laboratories Literature Lung Lung Inflammation Mediating Messenger RNA Molecular Target Mus Nucleotides Pathogenesis Pathway interactions Peptides Phagocytosis Plasminogen Activator Inhibitor 1 Play Pneumonia Process Production Protein p53 Proteins Publishing Regulation Regulatory Pathway Role Sepsis Specificity System TP53 gene Testing Therapeutic Time Tobacco smoke United States Work airway epithelium airway inflammation airway remodeling alveolar type II cell base cell injury in vitro testing in vivo inhibitor/antagonist injured airway insight lung injury macrophage neutrophil new therapeutic target novel novel strategies novel therapeutic intervention programs protective effect public health relevance repaired research study response

项目摘要

DESCRIPTION (provided by applicant): Our hypothesis is that tobacco smoke (TS) exposure (TSE) promotes apoptosis of airway epithelial cells through a newly identified regulatory pathway that involves induction of plasminogen activator inhibitor (PAI) -1 through posttranscriptional stabilization of PAI-1 mRNA by p53. This hypothesis is supported by our preliminary data and extends a mature body of literature that implicates epithelial cell injury and the participation of the fibrinolytic pathway in the pathogenesis of a wide range of lung injuries, including COPD and airway remodeling induced by TSE. While prior studies implicate p53 protein in airway epithelial cell damage and strongly suggest that the PAI-1 plays a key role in the pathogenesis of increased airway reactivity, the role of PAI-1 in TSE-induced airway injury remains unclear at the present time. Our objectives are to determine how PAI-1 expression is controlled by TSE-induced p53 and elucidate the mechanism by which this pathway affects airway epithelial cell apoptosis. We will then block TSE-mediated induction of PAI-1 to reverse airway and alveolar epithelial cell apoptosis due to TSE. We will apply both in vitro and in vivo approaches to achieve these objectives. We will determine the responses of primary cultures of human small airway epithelial or alveolar type (AT) II cells to TSE in vitro and test the specificity of the responses in parallel studies in which we will test the responses of primary ATII cells isolated from mouse lungs. We will next determine the effects of TSE in WT, p53-/- and PAI-1-/- mice to elucidate the effect of p53-mediated expression of PAI-1 on lung epithelial cell apoptosis in vivo. Our specific aims are: 1. To determine the mechanism by which p53-induced PAI-1, and inhibition of PAI-1 expression, modulate airway and alveolar epithelial cell apoptosis in vitro. 2. To determine how p53-induced PAI-1 and inhibition of PAI-1 expression contribute to LEC apoptosis during TSE-induced lung injury in vivo. These studies address a critical gap in current knowledge about how the fibrinolytic system regulates TSE-induced airway damage via interaction of PAI-1 mRNA with p53. This project extends the ongoing translational work of our laboratory to a clinically important new area. We will deploy our expertise in the area of posttranscriptional mechanisms to now elucidate how p53-mediated PAI-1 expression by the airway epithelium regulates epithelial apoptosis that characterizes airway remodeling induced by TSE. These studies will accelerate the development of novel therapeutic interventions to mitigate lung epithelial injury. PUBLIC HEALTH RELEVANCE: Tobacco smoke exposure (TSE) damages the airway lining otherwise called the lung epithelium. TSE-induced damage to the lining of the lungs characterizes chronic obstructive lung disease (COPD) which is the fourth leading cause of death in the United States. Our findings and those of the literature suggest that TSE-induced airway injury involves programmed airway epithelial cell death, airway inflammation and abnormal fibrin turnover. In this project, we will determine how p53, a protein causing epithelial cell death, regulates PAI-1, an inhibitor of the blood clot dissolution system, to influence the viability of the airway epithelium. These studies will enable us to understand the role of newly identified interactions between p53 and PAI-1 in the pathogenesis of lung epithelial cell injury and airway remodeling and will accelerate the development of new strategies to protect the airways against TSE-mediated damage.

描述（由申请人提供）：我们的假设是，烟草烟雾（TS）暴露（TSE）通过新发现的调节途径促进气道上皮细胞凋亡，该途径涉及通过转录后稳定PAI-1来诱导纤溶酶原激活剂抑制剂（PAI）-1 1 p53 的 mRNA。这一假设得到了我们的初步数据的支持，并扩展了一系列成熟的文献，这些文献表明上皮细胞损伤和纤溶途径参与了多种肺损伤的发病机制，包括 COPD 和 TSE 诱导的气道重塑。虽然先前的研究表明 p53 蛋白与气道上皮细胞损伤有关，并强烈表明 PAI-1 在气道反应性增加的发病机制中发挥着关键作用，但 PAI-1 在 TSE 诱导的气道损伤中的作用目前仍不清楚。我们的目标是确定 TSE 诱导的 p53 如何控制 PAI-1 表达，并阐明该途径影响气道上皮细胞凋亡的机制。然后，我们将阻断 TSE 介导的 PAI-1 诱导，以逆转 TSE 引起的气道和肺泡上皮细胞凋亡。我们将应用体外和体内方法来实现这些目标。我们将在体外确定人小气道上皮细胞或肺泡 II 型细胞的原代培养物对 TSE 的反应，并在平行研究中测试反应的特异性，其中我们将测试从小鼠肺部分离的原代 ATII 细胞的反应。接下来我们将确定 TSE 对 WT、p53-/- 和 PAI-1-/- 小鼠的影响，以阐明 p53 介导的 PAI-1 表达对体内肺上皮细胞凋亡的影响。我们的具体目标是： 1. 确定p53诱导PAI-1以及抑制PAI-1表达在体外调节气道和肺泡上皮细胞凋亡的机制。 2. 确定p53诱导的PAI-1和PAI-1表达的抑制如何在TSE诱导的体内肺损伤期间导致LEC凋亡。这些研究解决了当前关于纤溶系统如何通过 PAI-1 mRNA 与 p53 相互作用调节 TSE 诱导的气道损伤的知识空白。该项目将我们实验室正在进行的转化工作扩展到临床上重要的新领域。我们将利用我们在转录后机制领域的专业知识来阐明 p53 介导的气道上皮 PAI-1 表达如何调节上皮细胞凋亡，从而表征 TSE 诱导的气道重塑。这些研究将加速开发新的治疗干预措施，以减轻肺上皮损伤。公共卫生相关性：烟草烟雾暴露 (TSE) 会损害气道内壁（也称为肺上皮）。 TSE 引起的肺内膜损伤是慢性阻塞性肺病 (COPD) 的特征，慢性阻塞性肺病是美国第四大死因。我们的研究结果和文献表明，TSE 引起的气道损伤涉及程序性气道上皮细胞死亡、气道炎症和纤维蛋白更新异常。在这个项目中，我们将确定 p53（一种导致上皮细胞死亡的蛋白质）如何调节 PAI-1（一种血栓溶解系统抑制剂），从而影响气道上皮的活力。这些研究将使我们能够了解新发现的 p53 和 PAI-1 之间的相互作用在肺上皮细胞损伤和气道重塑发病机制中的作用，并将加速开发新策略来保护气道免受 TSE 介导的损伤。