Extracellular Matrix Components, Oxidants and Antioxidants in Pulmonary Fibrosis

肺纤维化中的细胞外基质成分、氧化剂和抗氧化剂

基本信息

批准号：
7503397
负责人：
Corrine R Kliment
金额：
$ 4.6万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7503397
关键词：
Alveolar Antioxidants Asbestos Asbestosis Binding Biochemical Biological Assay Breathing Cells Chemotactic Factors Chemotaxis Collagen Disease Enzymes Extracellular Matrix Fiber Fibrosis Glycosaminoglycans Heparin Heparitin Sulfate Human Hyaluronic Acid Immunohistochemistry In Vitro Inflammation Inflammatory Inflammatory Response Injury Interstitial Lung Diseases Knock-out Knowledge Laboratories Lead Link Liquid substance Localized Lung Matrilysin Matrix Metalloproteinases Mediating Mediator of activation protein Membrane Mineral Fibers Modeling Morbidity - disease rate Mus Oxidants Oxidative Stress Pathogenesis Pathology Pneumoconiosis Process Pulmonary Fibrosis Role Side Superoxide Dismutase System Testing Therapeutic Intervention Thinking Tissues Transgenic Mice Transgenic Organisms Western Blotting Wild Type Mouse Work cell motility chemokine cytokine day extracellular in vivo interstitial lung injury mortality neutrophil prevent prototype receptor response syndecan

项目摘要

DESCRIPTION (provided by applicant): Asbestosis is a debilitating form of pneumoconiosis and interstitial lung disease caused by the inhalation of asbestos fibers. Asbestosis results in fibrotic pathology, which causes significant morbidity and mortality. Inflammation and oxidative stress are known to contribute to the pathogenesis of this disease. Extracellular superoxide dismutase (EC-SOD) is antioxidant enzyme highly expressed in the lung and has been shown to protect the lung from oxidant-mediated damage, inflammation, and interstitial fibrosis. However, the mechanisms through which EC-SOD inhibits pulmonary fibrosis and inflammation remain unclear. Extracellular matrix (ECM) components, such as collagen and glycosaminoglycans, are highly sensitive to oxidative fragmentation and become potent chemoattractants for inflammatory cells. EC-SOD is known to tightly bind and localize to the glycosoaminoglycan, heparan sulfate (HS). The hypothesis of this proposal is that one mechanism in which EC-SOD protects the lung from oxidant-induced damage, inflammation, and fibrosis is by preventing oxidative fragmentation of Heparin/Heparan Sulfate (HS) in the ECM. The proposed studies will utilize in vitro heparin/HS fragmentation assays to study the protective role of EC-SOD and chemotaxis assays to analyze inflammatory responses to oxidatively fragmented heparin/HS and EC- SOD. Finally, wild type mice, EC-SOD knockout and EC-SOD over-expressing transgenic mice will be used to study the in vivo role of EC-SOD and HS in the lungs of asbestos- versus control-treated mice through biochemical and histological analysis.

描述（由申请人提供）：石棉沉着症是一种因吸入石棉纤维而引起的尘肺病和间质性肺病，使人衰弱。石棉沉着症会导致纤维化病理，从而导致显着的发病率和死亡率。已知炎症和氧化应激导致这种疾病的发病机制。细胞外超氧化物歧化酶 (EC-SOD) 是一种在肺部高表达的抗氧化酶，已被证明可以保护肺部免受氧化剂介导的损伤、炎症和间质纤维化。然而，EC-SOD抑制肺纤维化和炎症的机制仍不清楚。细胞外基质 (ECM) 成分，例如胶原蛋白和糖胺聚糖，对氧化断裂高度敏感，并成为炎症细胞的有效化学引诱剂。众所周知，EC-SOD 与糖胺聚糖硫酸乙酰肝素 (HS) 紧密结合并定位。该提议的假设是，EC-SOD 保护肺免受氧化剂诱导的损伤、炎症和纤维化的一种机制是通过防止 ECM 中肝素/硫酸乙酰肝素 (HS) 的氧化断裂。拟议的研究将利用体外肝素/HS碎片测定来研究EC-SOD的保护作用，并利用趋化性测定来分析对氧化碎片肝素/HS和EC-SOD的炎症反应。最后，将使用野生型小鼠、EC-SOD 敲除小鼠和 EC-SOD 过表达转基因小鼠，通过生化和组织学分析，研究 EC-SOD 和 HS 在石棉处理小鼠与对照处理小鼠肺部的体内作用。