PDF(Pubmed)
Abstract：
Paraquat (PQ) is a widely used herbicide and a common cause of poisoning that leads to pulmonary fibrosis with a high mortality rate. However, the underlying mechanisms of PQ-induced pulmonary fibrosis and whether pulmonary epithelial cell senescence is involved in the process remain elusive. In this study, PQ-induced pulmonary epithelial cell senescence and Hippo-YAP/TAZ activation were observed in both C57BL/6 mice and human epithelial cells. PQ-induced senescent pulmonary epithelial cells promoted lung fibroblast transformation through secreting senescence-associated secretory phenotype (SASP) factors. Yap/Taz knockdown in mice lungs significantly decreased the expression of downstream profibrotic protein Ctgf and senescent markers p16 and p21, and alleviated PQ-induced pulmonary fibrosis. Interfering YAP/TAZ in senescent human pulmonary epithelial cells resulted in decreased expression of the anti-apoptosis protein survivin and elevated level of apoptosis. In conclusion, our findings reveal a novel mechanism by which the involvement of Hippo-YAP/TAZ activation in pulmonary epithelial cell senescence mediates the pathogenesis of PQ-induced pulmonary fibrosis, thereby offering novel insights and potential targets for the clinical management of PQ poisoning as well as providing the mechanistic insight of the involvement of Yap/Taz activation in cell senescence in pulmonary fibrosis and its related pulmonary disorders. The YIN YANG balance between cell senescence and apoptosis is important to maintain the homeostasis of the lung, the disruption of which will lead to disease.
摘要：
百草枯（PQ）是一种广泛使用的除草剂，是导致肺纤维化的常见中毒原因，死亡率高。然而,PQ诱导肺纤维化的潜在机制以及肺上皮细胞衰老是否参与该过程仍不清楚。在这项研究中,在C57BL/6小鼠和人上皮细胞中均观察到PQ诱导的肺上皮细胞衰老和Hippo-YAP/TAZ激活。PQ诱导的衰老肺上皮细胞通过分泌衰老相关分泌表型（SASP）因子促进肺成纤维细胞转化。小鼠肺内Yap/Taz敲低可显著降低下游促纤维化蛋白Ctgf和衰老标志物p16、p21的表达,减轻PQ诱导的肺纤维化。在衰老的人肺上皮细胞中干扰YAP/TAZ导致抗凋亡蛋白survivin的表达降低和凋亡水平升高。总之,我们的发现揭示了一种新的机制，通过该机制，Hippo-YAP/TAZ激活参与肺上皮细胞衰老介导PQ诱导的肺纤维化的发病机理，从而为PQ中毒的临床管理提供了新的见解和潜在的目标，并提供了Yap/Taz激活参与肺纤维化及其相关肺部疾病的细胞衰老的机制见解。阴阳平衡细胞衰老和凋亡对维持肺的内环境稳定,破坏会导致疾病。
