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

• 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
• 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

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(申请人提供)：我们的假设是，烟草烟雾(TS)暴露(TSE)通过一种新发现的调控途径促进呼吸道上皮细胞的凋亡，该调控途径涉及通过P53转录后稳定PAI-1mRNA而诱导纤溶酶原激活物抑制物(PAI)-1。这一假说得到了我们初步数据的支持，并扩展了一系列成熟的文献，这些文献涉及上皮细胞损伤和纤溶途径参与了一系列肺损伤的发病机制，包括COPD和TSE诱导的气道重塑。虽然先前的研究表明P53蛋白参与了气道上皮细胞损伤，并强烈表明PAI-1在气道反应性增强的发病机制中发挥了关键作用，但PAI-1在TSE诱导的气道损伤中的作用目前尚不清楚。我们的目标是确定TSE诱导的P53如何调控PAI-1的表达，并阐明这一途径影响呼吸道上皮细胞凋亡的机制。然后，我们将阻断TSE介导的PAI-1的诱导，以逆转TSE引起的呼吸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。我们将在体外测定原代培养的人小气道上皮细胞或肺泡型(AT)II细胞对TSE的反应，并在平行研究中测试从小鼠肺中分离的ATII细胞的反应。接下来，我们将检测TSE对WT、P53-/-和PAI-1-/-小鼠的影响，以阐明P53介导的PAI-1在体内对肺上皮细胞凋亡的影响。我们的具体目标是：1.探讨P53诱导PAI-1及抑制PAI-1表达对体外培养的大鼠呼吸道和肺泡上皮细胞凋亡的影响机制。2.探讨P53诱导的PAI-1及PAI-1表达抑制在TSE诱导的肺损伤中肺内皮细胞凋亡中的作用。这些研究解决了目前关于纤溶系统如何通过PAI-1mRNA与P53的相互作用调节TSE诱导的呼吸道损伤的关键知识空白。该项目将我们实验室正在进行的翻译工作扩展到一个具有临床重要性的新领域。我们将运用我们在转录后机制领域的专业知识，现在阐明P53介导的PAI-1在气道上皮细胞中的表达如何调节上皮细胞凋亡，这是TSE诱导的气道重塑的特征。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。 与公共健康相关：烟草烟雾暴露(TSE)会损害呼吸道衬里，也就是肺上皮。慢性阻塞性肺病(COPD)是美国第四大死因，由TSE引起的对肺部内层的损伤是其特征。我们的发现和文献表明，TSE诱导的气道损伤包括气道上皮细胞程序性死亡、气道炎症和纤维蛋白代谢异常。在这个项目中，我们将确定导致上皮细胞死亡的蛋白质P53如何调节血栓溶解系统的抑制物PAI-1，从而影响呼吸道上皮细胞的活性。这些研究将使我们能够理解新发现的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，并将加速开发新的策略来保护呼吸道免受TSE介导的损伤。