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

纤溶酶原激活剂抑制剂 1 对二氧化硅诱导的肺损伤的调节

• 批准号: 10370063
• 负责人: Sreerama Shetty
• 金额: $ 40.43万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10370063
• 关键词: Address; Agriculture; Alveolar; Alveolar Cell; Animal Model; Apoptosis; Autophagocytosis; Belief; CCL2 gene; Catalytic Domain; Cell Survival; Cessation of life; Chronic; Clinical; Clinical Trials; Coal; Data; Deposition; Development; Diagnosis; Dust; Environmental Exposure; Epithelial Cells; Exposure to; Fibrinolysis; Fissural; Floor; Gases; Gold; Human; Inflammatory; Inhalation; Injury; Interleukin-17; Interleukins; Interruption; Intervention; Intraperitoneal Injections; Knowledge; Length; Lung diseases; Lysosomes; Mechanics; Mediating; Mining; Molecular; Monocyte Chemoattractant Proteins; Morbidity - disease rate; Mus; Nebulizer; Occupational Exposure; Oils; Particulate Matter; Pathogenesis; Pathway interactions; Patients; Peptides; Persons; Plasminogen Activator Inhibitor 1; Process; Protein phosphatase; Proteins; Public Health; Publications; Publishing; Pulmonary Fibrosis; Pulmonary Inflammation; Quartz; Regulation; Research; Risk Factors; Role; Signal Transduction; Silicon Dioxide; Silicosis; Structure of parenchyma of lung; System; TP53 gene; Tertiary Protein Structure; Testing; Transgenic Mice; Tumor Suppressor Proteins; Up-Regulation; Urokinase; Work; alveolar epithelium; base; caveolin 1; cell injury; commercialization; crystallinity; cytokine; epidemiology study; fibrotic lung; granite; hydraulic fracturing; innovation; lung development; lung injury; mitochondrial dysfunction; mouse model; novel; novel strategies; overexpression; pre-clinical; prevent; scaffold; urokinase inhibitor

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.

职业或环境暴露于可呼吸的结晶二氧化硅灰尘是肺部疾病的主要原因 全世界。这发生在采矿，喷砂，铸造厂，农业，建筑，以及最近的石油 和气体提取，涉及氢化断裂。预计在美国暴露于二氧化硅，因为 用作维护的支撑剂的数百万磅的晶体二氧化硅（“冰冻砂”）的机械处理 页岩或石油沉积物的水解压裂产生的裂缝和裂缝以及花岗岩的加工或 地板和台面中的夸脱。但是，导致硅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理 肺纤维化（SPF）或硅氧症可能对工人和公共卫生具有广泛的影响。增加类型 II肿瘤抑制蛋白介导的肺泡上皮细胞（A2C）损伤，p53通过上调 纤溶酶原激活剂抑制剂1（PAI-1）与SLI强有关。此外，提高了促值的表达 炎症细胞因子；白介素17a（IL-17A）在SLI期间，增加单核细胞趋化蛋白诱导的 蛋白质1（MCPIP1）。尽管多项研究强调了IL-17A，MCPIP1和PAI-1的重要性 自噬失调在硅发病机理中，相互关系的信息有限 在IL-17A，MCPIP1，PAI-1和自噬的控制之间增加。 我们的建议将解决这一重要的知识差距。我们将使用一系列分子和新颖 介入的方法，包括使用转基因小鼠来解决我们的工作假设；那个 17a介导的MCPIP1和PAI-1表达诱导促进了异常的自噬；尤其 线粒体，因此在A2C中凋亡，这对于SLI和硅化的发病机理至关重要。我们的 目的是确定如何通过MCPIP1进行IL-17A诱导的PAI-1表达的变化，调节自噬 和A2CS的凋亡以及硅。我们将确定是否针对7-mer删除的该途径 Caveolin-1脚手架肽（CSP7）的碎片可减轻SLI和重塑。 我们的具体目的是：1）阐明IL-17A诱导的PAI-1在自噬中的作用 SLI的小鼠模型，并确定是否可以通过用CSP7处理来逆转硅化。 2）到 确定IL17A诱导的PAI-1是否介导SLI的小鼠中的线粒体及其通过CSP7缓解措施 治疗。该项目将通过阐明IL-17A如何介导MCPIP1，PAI-1的诱导来推进该领域 自噬可降低A2C的生存能力，从而导致二氧化硅暴露引起的肺损伤和纤维化。这个建议 将扩大我们对硅发病机理的理解，并测试一种新的介入方法来减轻 SLI并降低其长期发病率。