EXTRACELLULAR SUPEROXIDE DISMUTASE IN PULMONARY FIBROSIS

间质性肺纤维化是一种对肺损伤具有潜在致命性的慢性反应。尽管参与间质性肺纤维化发病的生化机制尚不清楚，但已知在炎症反应中发挥作用的活性氧被认为参与了该病的进展。已有研究表明，抗氧化酶--细胞外超氧化物歧化酶(EC-SOD)可以预防肺纤维化的进展。为了验证EC-SOD在这种疾病中起中心作用的假设，过度表达EC-SOD的转基因小鼠和不表达EC-SOD的基因敲除小鼠将被用于博莱霉素诱导的肺纤维化模型。我们将确定转基因和基因敲除小鼠中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，我们将检测EC-SOD在纤维化损伤早期的表达和/或生物分布，以确定在疾病发展早期EC-SOD活性的变化是否在肺纤维化的发病机制中起关键作用。最后，我们将在我们的模型中检查一氧化氮、超氧化物歧化酶和EC-SOD的交互作用，以确定一氧化氮是否参与了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.