EXTRACELLULAR SUPEROXIDE DISMUTASE IN PULMONARY FIBROSIS

肺间质纤维化是一种潜在的致死性慢性肺损伤反应。尽管间质性肺纤维化发病机制的生化机制尚不清楚，但已知在炎症反应中起作用的活性氧被认为参与了该疾病的进展。有研究认为，抗氧化酶细胞外超氧化物歧化酶（EC-SOD）可以防止肺纤维化的进展。为了验证EC-SOD在该疾病中起核心作用的假设，将在博来霉素诱导的肺纤维化模型中使用过表达EC-SOD的转基因小鼠和不表达EC-SOD的敲除小鼠。我们将确定转基因和基因敲除小鼠EC-SOD水平的改变是否会改变对博莱霉素诱导的肺损伤的反应。此外，我们将在纤维化损伤的早期阶段检测EC-SOD的表达和生物分布，以确定在疾病发展早期EC-SOD活性的改变是否对肺纤维化的发病机制至关重要。最后，我们将在我们的模型中检查一氧化氮、超氧化物和EC-SOD的相互作用，以确定一氧化氮是否参与与肺纤维化相关的氧化损伤。

Interstitial pulmonary fibrosis is a potentially lethal, chronic response to lung injury. Although the biochemical mechanisms involved in the pathogenesis of interstitial pulmonary fibrosis are poorly understood, reactive oxygen species, which are known to play a role in inflammatory reactions, are believed to be involved in the progression of this disease. It has been proposed that the antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), can protect against the progression of pulmonary fibrosis. To test the hypothesis that EC-SOD plays a central role in this disease, transgenic mice that overexpress EC-SOD and knockout mice that do not express EC-SOD will be utilized in a model of bleomycin- induced pulmonary fibrosis. We will determine whether altered levels of EC-SOD in transgenic and knockout mice alters the response to bleomycin-induced lung injury. In addition, we will examine EC-SOD expression and1or biodistribution during the early stages of fibrotic injury, to determine if alterations in EC-SOD activity early in the development of the disease are critical to the pathogenesis of pulmonary fibrosis. Finally, we will examine the interactive effects of nitric oxide, superoxide and EC-SOD in our model to determine if nitric oxide is involved in the oxidative damage associated with pulmonary fibrosis.