Extracellular Matrix Components, Oxidants and Antioxidants in Pulmonary Fibrosis

描述（由申请人提供）：石棉肺是一种因吸入石棉纤维而导致的尘肺和间质性肺病。石棉沉着症导致纤维化病理学，其导致显著的发病率和死亡率。炎症和氧化应激是已知的，有助于这种疾病的发病机制。细胞外超氧化物歧化酶（EC-SOD）是在肺中高度表达的抗氧化酶，并且已显示保护肺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尚不清楚。细胞外基质（ECM）成分，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物。已知EC-SOD紧密结合并定位于糖氨基聚糖硫酸乙酰肝素（HS）。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。拟定的研究将利用体外肝素/HS片段化试验研究EC-SOD的保护作用，并利用趋化试验分析对氧化片段化肝素/HS和EC-SOD的炎症反应。最后，野生型小鼠，EC-SOD基因敲除和EC-SOD过表达转基因小鼠将被用来研究在体内作用的EC-SOD和HS在石棉与对照处理的小鼠的肺，通过生化和组织学分析。

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.