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.
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