miR-155在温石棉致人肺成纤维细胞表型变化中的表达及作用机制研究

Chrysotile asbestos has still been extensively mined and used in China due to its valuable properties in heat resistance and insulation. However, various epidemiological and toxicological studies have suggested that inhalation of chrysotile asbestos causes pulmonary fibrosis, which could mainly be attributed to the proliferation, migration and activation of pulmonary fibroblasts. Since their discovery less than a decade ago, microRNAs have been recognized as key regulators of gene expression and believed to participate in a variety of critical biological processes including cell proliferation, differentiation, and metabolic regularity. Although considerable attention has focused on the impact of microRNAs on tumorigenesis and immunological diseases, few studies have correlated them with pulmonary fibrosis. The expression of miR-155, which has been related to bleomycin-induced idiopathic pulmonary fibrosis, was found increased in human pulmonary fibroblasts exposed to either high concentrations or low concentrations of chrysotile asbestos. In this study, by investigations on the relationship among miR-155 expression, BMP signaling pathway and alteration of fibroblast induced by chrysotile asbestos, we will look into the mechanism underlying miR-155 regulation of BMP signaling pathway as well as its involvement in the altered fibroblast phenotype due to a chrysotile asbestos exposure, and get a better understanding of possible regulatory roles of miR-155 in pulmonary fibrosis, which will facilitate the implementation of early intervention strategies for pulmonary diseases related to chrysotile asbestos exposure.

温石棉由于其无可替代的优良性能，目前在我国仍被广泛开采和使用。然而多项流行病学研究和毒理学研究都证实温石棉吸入可导致肺纤维化病变，而成纤维细胞的增殖、迁移和活化是温石棉诱导肺纤维化一系列复杂事件中的重要环节。microRNA作为一类重要的信号调控分子，具有广泛多样的生物学功能。但目前有关microRNA在温石棉致肺纤维化病变中的作用研究较少。本研究拟通过检测miR-155在温石棉处理的人肺成纤维细胞中的表达改变，及其在温石棉致人肺成纤维细胞增殖迁移等表型变化中的调控，对miR-155与肺纤维化的关系进行初步探讨。通过研究miR-155对BMP信号通路的调控机制及其是否通过该通路调控温石棉引起的细胞表型改变，进一步了解miR-155在肺纤维化病变过程中可能的调控机制。这将有助于我们以microRNA调控机制为基础，为温石棉所致肺部疾病早期干预措施的提出提供重要的理论依据。

究和毒理学研究都证实温石棉吸入可导致肺纤维化病变，成纤维细胞的增殖、迁移和活化是温石棉诱导肺纤维化一系列复杂事件中的重要环节。TGF-β由于其已知的致纤维化作用，在这一过程中发挥重要的作用。本研究通过检测miR-155在人肺成纤维细胞中的表达情况，及其在人肺成纤维细胞增殖迁移等表型变化中的调控，发现TGF-β处理可引起miR-155表达下调，过表达miR-155可抑制TGF-β引起的成纤维细胞增殖迁移、胶原合成增加等表型改变。通过研究miR-155对BMP信号通路SMAD1等关键分子的表达调控作用，发现miR-155表达抑制与BMP抑制剂Gremlin处理对这些分子的调控作用相近，说明miR-155在BMP信号通路传导过程中起着重要的调控作用。由于BMP信号通路已被证实具有一定的肺纤维化抑制作用，因此该结果也证实miR-155对于BMP信号通路发挥肺纤维化抑制作用的重要性，miR-155可能通过作用于BMP信号通路影响肺纤维化的病理过程，具体的调控机制还有待进一步研究。上述发现提示我们miR-155可能具有一定的肺纤维化抑制作用，有助于我们以miRNA调控机制为基础，为温石棉所致肺部疾病早期干预措施的提出提供重要的理论依据。