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

职业或环境暴露于可呼吸的结晶二氧化硅粉尘是肺部疾病的主要原因。 全世界。这种情况发生在采矿、喷砂、铸造、农业、建筑业以及最近的石油行业。 以及天然气开采，这涉及到水力压裂。美国接触二氧化硅的风险预计将上升，因为 机械处理数百万磅的结晶二氧化硅(“压裂砂”)作为支撑剂，以保持 页岩或岩油矿床水力压裂和花岗岩或矿石加工产生的裂缝 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)或二氧化硅诱导的潜在发病机制 肺纤维化(SPF)或矽肺可能会对工人和公众健康产生广泛影响。增强型 抑癌蛋白P53上调肺泡上皮细胞损伤的研究 纤溶酶原激活物抑制物-1(PAI-1)与系统性红斑狼疮密切相关。此外，亲本的表达增加- 炎性细胞因子；白介素17A(IL-17A)在SLI期间增强单核细胞趋化蛋白 蛋白1(MCPIP1)。尽管，多项研究强调了IL-17A、MCPIP1和PAI-1的重要性，以及 自噬失调在矽肺发病机制中的作用，关于两者之间相互关系的信息有限 IL-17A、MCPIP1、PAI-1升高与自噬控制之间的关系。 我们的建议将解决这一严重的知识差距。我们将使用一系列的分子和新奇 干预方法，包括使用转基因小鼠来解决我们的工作假说；IL-1 17A介导的MCPIP1和PAI-1表达促进异常自噬； A2Cs的有丝分裂和细胞凋亡是SLI和矽肺发病机制的核心。我们的 目的：探讨MCPIP1在IL-17A诱导的PAI-1表达中的变化及其对自噬的调节作用 以及A2Cs中的细胞凋亡，从而导致矽肺。我们将确定是否通过7-聚体缺失来靶向这条途径 小窝蛋白-1支架多肽片段(CSP7)可减轻SLI和重塑。 我们的具体目的是：1)阐明IL-17A诱导的PAI-1在调节细胞自噬中的作用 建立系统性红斑狼疮的小鼠模型，并确定CSP7治疗能否逆转矽肺。2)至 IL-17A诱导的PAI-1是否介导SLI小鼠有丝分裂及CSP7的抑制作用 治疗。该项目将通过阐明IL-17A如何介导MCPIP1、PAI-1的诱导来推动该领域的发展 自噬降低了A2C的活性，导致肺损伤和二氧化硅暴露导致的纤维化。这项建议 将扩大我们对矽肺发病机制的了解，并测试一种新的干预方法来缓解 减少SLI的长期发病率。

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.