百草枯中毒致肺纤维化中TGF-β1/CTGF信号转导通路的作用机制研究

百草枯是目前全球使用最广的除草剂之一，肺脏是其中毒的主要靶器官，表现为早期的急性肺损伤，晚期的肺泡和间质纤维化，被命名为"百草枯肺"，呼吸衰竭是其死因，病死率达60%～87.5%。迄今中毒机制不明，亦无有效拮抗药物。本研究拟通过整体动物模型和体外细胞培养实验，从整体、细胞和分子水平探讨百草枯致肺纤维化的分子机制，找出百草枯致肺纤维化的关键点，尤其是阐明结缔组织生长因子(CTGF)在百草枯致肺纤维化过程中的作用，及转化生长因子β1(TGF-β1)介导的信号转导通路对CTGF表达的调控机制。探讨CTGF作为百草枯致肺纤维化治疗的新靶点的可行性，进一步补充和完善百草枯肺脏毒作用机制，以期为百草枯中毒的有效治疗途径提供理论基础和新的线索。

Paraquat (PQ) (1,10-dimethyl-4,40-bipyridinium dichloride), which is used world-widely for its high efficiency and low residues in the crops as a non-selective contact herbicide, can cause severe lung injury in humans and experimental animals. PQ-induced lung injury is characterized by initial destructive phase of pulmonary edema, alveolar hemorrhage, inflammatory infiltration, and second proliferative phase of fibroblast proliferation, excessive collagen deposition, which eventually results in pulmonary fibrosis and respiratory failure. So far, the mechanism of PQ toxicity is poorly understood and therapeutics has been disappointing and the mortality still remains high.This study investigate the dynamic changes of biomarkers of transcriptional factors NF-kB and related cytokines, TGF-β1 and its target gene CTGF over time, in order to explore the key points of PQ-induced pulmonary fibrosisi mechanisms, especially the role and regulation of CTGF by TGF-β1-mediated signal transduction pathways through rat model and in vitro culture. Moreover, we aimed to observe the effect of RNA interfernce for CTGF as target gene on PQ-induced pulmonary fibrosis and evaluate its potential therapeutic effect to provide scientific basis and new clues for the treatment strategy of PQ poisoning.