Regulation of Silica-induced Lung Injury by Plasminogen Activator Inhibitor-1

职业或环境暴露于可吸入结晶二氧化硅粉尘是肺部疾病的主要原因 国际吧这发生在采矿，喷砂，铸造工作，农业，建筑和最近在石油 和天然气开采，包括水力压裂。预计美国的二氧化硅暴露量将上升， 机械处理数百万磅的结晶二氧化硅（“压裂砂”），用作支撑剂， 页岩或岩石石油矿床的水力压裂和花岗岩加工产生的裂缝和裂缝， 地板和台面上的夸脱。然而，导致矽肺的基本机制仍然存在， 难以捉摸。了解二氧化硅诱导的肺损伤（sLI）或二氧化硅诱导的 肺纤维化（sPF）或矽肺可能对工人和公众健康产生广泛影响。增加型 II肺泡上皮细胞（A2 C）损伤介导的肿瘤抑制蛋白，p53通过上调 纤溶酶原激活物抑制剂-1（派-1）与sLI密切相关。此外，增加的前- 炎症细胞因子;白细胞介素-17A（IL-17 A）在sLI期间，增强单核细胞趋化蛋白诱导的 蛋白1（MCPIP 1）。尽管多项研究强调了IL-17 A、MCPIP 1和派-1的重要性， 自噬失调在硅肺发病机制中的作用，关于自噬失调与硅肺发病机制之间的相互关系的信息有限。 IL-17 A、MCPIP 1、派-1的增加与自噬的控制之间的关系。 我们的建议将填补这一关键的知识空白。我们将使用一系列分子和新颖的 干预性方法，包括使用转基因小鼠来解决我们的工作假设; IL- 17 A介导的MCPIP 1和派-1表达诱导促进异常自噬;特别是 线粒体自噬和A2 Cs的凋亡，这是sLI和矽肺发病机制的核心。我们 目的是确定MCPIP 1如何改变IL-17 A诱导的派-1表达，调节自噬 以及A2 Cs的凋亡从而导致矽肺。我们将确定是否用7-mer缺失靶向该途径 小窝蛋白-1支架肽片段（CSP 7）减轻sLI和重塑。 我们的具体目的是：1）阐明IL-17 A诱导的派-1在自噬调节中的作用， sLI的小鼠模型，并确定是否可以通过用CSP 7治疗来逆转硅肺。2)到 确定IL 17 A诱导的派-1是否介导sLI小鼠的线粒体自噬及其通过CSP 7的缓解 治疗本项目将通过阐明IL-17 A如何介导MCPIP 1、派-1的诱导来推进该领域 并且自噬降低A2 C活力，导致由于二氧化硅暴露引起的肺损伤和纤维化。这项建议 将扩大我们对矽肺发病机制的理解，并测试一种新的干预方法，以减轻 降低其远期发病率。

Occupational or environmental exposure to respirable crystalline silica dusts is a major cause of lung diseases worldwide. This occurs in mining, sandblasting, foundry work, agriculture, construction and more recently in oil and gas extraction, which involves hydraulic fracturing. Exposure to silica is expected to rise in the US because of mechanical handling of millions of pounds of crystalline silica (“frac sand”) used as a proppant to maintain cracks and fissures created by hydraulic fracturing of shale or rock oil deposits and processing of granites or quarts in flooring and countertops. However, the fundamental mechanisms that contribute to silicosis remains elusive. Understanding the underlying pathogenesis of silica-induced lung injury (sLI) or silica-induced pulmonary fibrosis (sPF) or silicosis could have broad implications on workers’ and public health. Increased type II alveolar epithelial cell (A2C) damage mediated by the tumor suppressor protein, p53 via upregulation of plasminogen activator inhibitor-1 (PAI-1) is strongly implicated in sLI. Further, increased expression of a pro- inflammatory cytokine; interleukin-17A (IL-17A) during sLI, augments monocyte chemotactic protein-induced protein 1 (MCPIP1). Although, multiple studies underscore the importance of IL-17A, MCPIP1 and PAI-1, and dysregulated autophagy in the pathogenesis of silicosis, there is limited information on the interrelationships between increased IL-17A, MCPIP1, PAI-1 and control of autophagy. Our proposal will address this critical gap of knowledge. We will use a range of molecular and novel interventional approaches that include the use of transgenic mice to address our working hypothesis; that IL- 17A-mediated induction of MCPIP1 and PAI-1 expression promotes aberrant autophagy; in particular mitophagy and thereby apoptosis in A2Cs, which is central to the pathogenesis of sLI and silicosis. Our objective is to establish how changes in IL-17A-induced expression of PAI-1 by MCPIP1, regulates autophagy and apoptosis in A2Cs and thereby silicosis. We will determine if targeting of this pathway with a 7-mer deletion fragment of caveolin-1 scaffolding peptide (CSP7) mitigates sLI and remodeling. Our Specific Aims are: 1) To elucidate the role of IL-17A-induced PAI-1 in the regulation of autophagy in a mouse model of sLI and determine whether silicosis can be reversed by treatment with CSP7. 2) To determine if IL17A-induced PAI-1 mediates mitophagy in mice with sLI and its mitigation by CSP7 treatment. This project will advance the field by elucidating how IL-17A mediated induction of MCPIP1, PAI-1 and autophagy reduces A2C viability, resulting in lung injury and fibrosis due to silica exposure. This proposal will expand our understanding of the pathogenesis of silicosis and test a new interventional approach to mitigate sLI and decrease its long-term morbidity.