天然多酚白藜芦醇对尘肺肺纤维化的作用及机制研究

Pneumoconiosis accounts for 90% of reported occupational disease cases in China. It causes severe damage to the health of laboring force and the national economy, which makes it a major problem in public health. Pneumoconiosis is characterized as irreversible pulmonary fibrosis caused by dusts, which so far can not be cured. Resveratrol, a natural polyphenol product which exists in many dietary plants, has been reported to inhibit fibrosis in multiple fibrosis models. However, its effect on pneumoconiosis is unknown. In this study, the effect of resveratrol on pneumoconiosis will be determined in the rat disease model for the first time. There are several key steps during fibrosis, including inflammatory response, ROS production and epithelial mesenchymal transition. Therefore, the effect of resveratrol on these vital events will be evaluated in this proposed research. Given the facts that the expression of key cytokine TGF-β in fibrosis can be regulated by RNA regulator HuR, which will shuttle from nuclei to cytoplasm during polyphenol treatment, this study focuses on the mechanism of HuR mediated mRNA regulation in fibrosis during resveratrol treatment. This innovative investigation on effect and mechanism of resveratrol against pulmonary fibrosis in pneumoconiosis will help to understand the pathogenesis of pneumoconiosis more comprehensively and thereby creating a new sight in drug candidate development for pneumoconiosis treatment.

尘肺病占我国所有职业病的90%，严重损害劳动者健康，并给社会经济带来巨大损失，是目前我国公共卫生面临的巨大难题。尘肺病以肺部不可逆纤维化为特征，临床尚无有效治疗手段和药物。多酚类天然产物白藜芦醇，在肝、肾等多种纤维化疾病中表现出抑制纤维化的保护作用，而其对尘肺肺纤维化的作用及机制尚无研究。本项目将首次在尘肺病理进程中，探究白藜芦醇对肺纤维化的作用，通过研究肺纤维化的关键环节，包括炎症反应、ROS产生和上皮细胞间质化的影响，明确白藜芦醇的作用途径。另外，纤维化关键因子TGF-β的表达受到RNA调控因子HuR的调节，多酚类天然产物可以促使HuR发生标志性的核质迁移，因此本研究重点关注在白藜芦醇作用下，HuR及其介导的mRNA水平调控机制在尘肺纤维化进程中的作用。本项目通过研究白藜芦醇对尘肺纤维化的作用及相关分子机制，将更为全面地理解尘肺病的发病机理，并为寻找尘肺病新的候选药物开创全新视角。

尘肺病占我国职业病的90%，严重损害劳动者健康，并给社会经济带来巨大损失。尘肺病以肺部不可逆的纤维化为特征，临床尚无有效治疗手段。最近研究显示，多酚类天然产物白藜芦醇在肝、肾等多种纤维化疾病中表现出抑制纤维化的保护作用，然而其对肺纤维化的作用及机制尚缺乏研究。项目通过RT-PCR，western blot等分子生物学技术，主要研究白藜芦醇及与其结构类似的多酚类天然产物芹菜素对尘肺关键病理进程上皮细胞间质化（EMT）的作用及机制的研究。结果显示，芹菜素能通过调节EMT过程中关键标志基因表达，抑制TGF-β1诱导的肺泡上皮细胞EMT的发生。同时，通过与其他相关课题组的合作，项目还研究了小分子多肽D-4F对EMT 的作用，发现D-4F能延缓TGF-β1诱导的肺泡上皮细胞EMT的发生。. 另外，纤维化关键因子TGF-β1的表达受RNA调控因子HuR的调节，因此本项目还重点关注了HuR介导的调控机制在肺上皮细胞EMT过程中发挥的作用。通过RNAi，划痕实验等分子生物学和细胞生物学手段，证明HuR在EMT过程中通过调节EMT标志基因上游的转录因子的表达，抑制了EMT。由于EMT不仅是纤维化进程的关键步骤，也与肿瘤细胞迁移密切相关，因此还研究了HuR对肺癌上皮细胞迁移的作用，发现HuR能促进迁移。此外，本项目还通过建立二氧化硅诱导小鼠矽肺模型，研究了矽肺小鼠肺部转录组的变化。. 本项目的研究结果提示了芹菜素和小分子多肽D-4F作为延缓肺纤维化进程的药物的潜力，为进一步阐明 EMT发生机制提供了新的视角，同时，还能为其他类型纤维化疾病提供部分理论基础和创新依据。.