Liu Haijun, Fang Shencun, Wang Wei, Cheng Yusi, Zhang Yingming, Liao Hong, Yao Honghong, Chao Jie
Department of Physiology, School of Medicine, Southeast University, 87 Dingjiaqiao Rd, Nanjing, Jiangsu, 210009, China.
Neurobiology Laboratory, New Drug Screening Centre, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
Part Fibre Toxicol. 2016 Oct 25;13(1):55. doi: 10.1186/s12989-016-0167-z.
Silicosis is characterized by accumulation of fibroblasts and excessive deposition of extracellular matrix. Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) plays a critical role in fibrosis induced by SiO. However, the details of the downstream events of MCPIP1 activity in pulmonary fibrosis remain unclear. To elucidate the role of MCPIP1-induced autophagy in SiO-induced fibrosis, both the upstream molecular mechanisms and the functional effects of SiO on cell apoptosis, proliferation and migration were investigated.
Experiments using primary cultures of alveolar macrophages from healthy donors and silicosis patients as well as differentiated U937 macrophages demonstrated the following results: 1) SiO induced macrophage autophagy in association with enhanced expression of MCPIP1; 2) autophagy promoted apoptosis and activation of macrophages exposed to SiO, and these events induced the development of silicosis; 3) MCPIP1 facilitated macrophage apoptosis and activation via p53 signaling-mediated autophagy; and 4) SiO-activated macrophages promoted the proliferation and migration of fibroblasts via the MCPIP1/p53-mediated autophagy pathway.
Our results elucidated a link between SiO-induced fibrosis and MCPIP1/p53 signaling-mediated autophagy. These findings provide novel insight into the potential targeting of MCPIP1 or autophagy in the development of potential therapeutic strategies for silicosis.
矽肺的特征是成纤维细胞积聚和细胞外基质过度沉积。单核细胞趋化蛋白-1诱导蛋白1（MCPIP1）在二氧化硅诱导的纤维化中起关键作用。然而，MCPIP1活性在肺纤维化中的下游事件细节仍不清楚。为了阐明MCPIP1诱导的自噬在二氧化硅诱导的纤维化中的作用，我们研究了二氧化硅对细胞凋亡、增殖和迁移的上游分子机制及功能影响。
使用健康供体和矽肺患者的肺泡巨噬细胞原代培养物以及分化的U937巨噬细胞进行的实验得出以下结果：1）二氧化硅诱导巨噬细胞自噬，同时MCPIP1表达增强；2）自噬促进暴露于二氧化硅的巨噬细胞凋亡和激活，这些事件导致矽肺的发展；3）MCPIP1通过p53信号介导的自噬促进巨噬细胞凋亡和激活；4）二氧化硅激活的巨噬细胞通过MCPIP1/p53介导的自噬途径促进成纤维细胞的增殖和迁移。
我们的结果阐明了二氧化硅诱导的纤维化与MCPIP1/p53信号介导的自噬之间的联系。这些发现为矽肺潜在治疗策略开发中靶向MCPIP1或自噬的潜力提供了新的见解。
