硫辛酸是机体抗氧化防御网络的关键分子，表达受硫辛酸合成酶（Lias）基因调控，研究表明硫辛酸具有抗机体纤维化的作用。课题组前期研究发现矽尘诱导活性氧，促进肺纤维化。Nrf2在毒物诱导抗氧化防御机制中发挥核心作用。我们假设硫辛酸合成酶基因能够调控机体氧化应激网络，抑制Nrf2过度激活抗矽肺纤维化。为此，本研究采用新创建的能表达不同水平Lias基因的抗氧化小鼠模型，观察矽尘导致模型小鼠肺部病理及纤维化改变，定量揭示硫辛酸调控的内源性抗氧化水平与矽肺纤维化改变程度的关系。从蛋白质、mRNA水平等检测Lias、Nrf2及抗氧化酶HO-1、CAT、SOD、γ-GCS表达变化，阐明硫辛酸对矽肺纤维化的调控机制。并研究矽肺患者中Lias基因及其调控的抗氧化酶蛋白及mRNA表达规律，进行人群流行病学验证。本研究将对阐明矽肺纤维化的作用机制，发展新的诊断与治疗靶点，筛选抗氧化药物及个体化干预具有重要意义。

Lipoic acid is a key molecule in the antioxidant defense network, which is regulated by lipoic acid synthase gene. It has been shown to be resistant to fibrosis in many studies. We have found that SiO2 induces the reactive oxygen species, and it can promote pulmonary fibrosis. Nrf2 plays a key role in the antioxidation mechanism induced by exogenous toxic substances. We assume that lipoic acid can antagonize silicosis pulmonary fibrosis by regulation of oxidative stress network. Therefore, a new transgenic model mouse which can express lipoic acid synthase with different levels will be used in this study, The lung inflammatory, fibrosis related factors and pathological will be observed in pulmonary fibrosis in rat, and the relationship will be revealed between the endogenous antioxidant levels and pulmonary fibrosis induced by silicosis. The mechanism of fibrosis will be delineated through detection expression of Nrf2 and antioxidant enzymes which are regulated by lipoic acid such as HO-1, CAT, SOD, γ-GCS from protein and mRNA levels and protein localization. At the same time, the expression pattern of lipoic acid synthase gene and its related protein will enunciated in silicosis patients by epidemiological studies. This study is theoretically important in silicosis pulmonary fibrosis by elucidation the mechanism, development new diagnosis and treatment targets, screening of antioxidant drugs, individualized intervention of antioxidants.