EC-SOD in Asbestos-Induced Lung Injury

描述（由申请人提供）：石棉肺是由吸入石棉纤维引起的一种衰弱性间质性肺疾病，以肺泡间质炎症和纤维化为特征。石棉沉滞的发病机制尚不完全清楚，但活性氧（ROS）被认为起着核心作用。细胞外超氧化物歧化酶（EC-SOD）是一种抗氧化酶，在其他间质性肺疾病中保护肺，但尚未对石棉介导的疾病进行研究。该建议的假设是EC-SOD通过防止氧化损伤和基质金属蛋白酶（MMP）激活来保护石棉介导的肺损伤。这些研究将利用生化和组织学分析来研究石棉或对照处理小鼠肺中EC-SOD的存在。此外，EC-SOD敲除和转基因过表达小鼠将用石棉处理，以确定这种抗氧化剂的存在是否会影响疾病的严重程度。最后，实验将检验EC-SOD的存在是否会影响潜伏MMPs的激活，因为这些蛋白酶可以被ROS激活，并且已知在其他肺纤维化模型中有助于疾病进展。

DESCRIPTION (provided by applicant): Asbestosis is a debilitating interstitial lung disease caused by the inhalation of asbestos fibers and characterized by inflammation and fibrosis of alveolar interstitium. The pathogenesis of asbestosis is not fully understood, but reactive oxygen species (ROS) are thought to play a central role. Extracellular superoxide dismutase (EC-SOD) is an antioxidant enzyme that protects the lung in other interstitial lung diseases but has not been studied in asbestos-mediated disease. The hypothesis of this proposal is that EC-SOD protects against asbestos-mediated lung injury by preventing oxidative damage and matrix metalloproteinase (MMP) activation. These studies will utilize biochemical and histological analyses to study the presence of EC-SOD in the lungs of asbestos- or control-treated mice. In addition, EC-SOD knockout and transgenic overexpressing mice will be treated with asbestos to determine if the presence of this antioxidant affects disease severity. Finally, experiments will examine whether the presence of EC-SOD affects activation of latent MMPs since these proteases can become activated by ROS and are known to contribute to disease progression in other models of pulmonary fibrosis.