期刊
TOXICOLOGY LETTERS
卷 355, 期 -, 页码 150-159出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.toxlet.2021.11.015
关键词
Macrophage; Silica; Necroptosis; Inflammation; Pulmonary fibrosis; Silicosis
类别
资金
- University Natural Science Research Project of Anhui Province [KJ2019A0132, KJ2019ZD13]
- Open Research Fund of State Key Laboratory of Cellular Stress Biology at Xiamen University [SKLCSB2018kf016]
- University Synergy Innovation Program of Anhui Province [GXXT-2021-077]
The necroptotic signaling pathway of macrophages is significantly activated in the lungs of silicosis mouse models, promoting the progression of silicosis through enhancing lung inflammatory responses and fibrogenesis. Increased M1 macrophage infiltration and up-regulation of pro-inflammatory cytokines were observed in this study, along with the up-regulation of pro-fibrotic factors and fibrosis biomarkers, which were recovered by the specific inhibitor of RIP1 kinase-dependent necroptosis. These findings provide new insights for the treatment of silicosis.
Silicosis is a disease characterized by extensive lung nodules and fibrosis caused by the prolonged inhalation of silica in occupational settings. However, the molecular mechanism of silicosis development is complex and not fully understood. Furthermore, the role of necroptosis, a death receptor-mediated and caspase-independent mode of inflammatory cell death, is not well understood in silicosis. Here, we demonstrate that the necroptotic signaling pathway of macrophages is significantly activated in the lungs of silicosis mouse models. Meanwhile, increased M1 macrophage infiltration and up-regulation of pro inflammatory cytokines (TNF-alpha, IL-6) were observed in our silicosis model. Notably, the expression of the pro-fibrotic factor, TGF-beta 1, and fibrosis biomarkers alpha-SMA and collagen I were also unregulated; however, these phenomena were recovered by Nec-1, an inhibitor specific for RIP1 kinase-dependent necroptosis. We conclude that macrophage-mediated necroptosis promotes the progression of silicosis by enhancing lung inflammatory responses and fibrogenesis in a mouse model of silicosis. These findings provide new insights for drug discovery and clinical treatment of silicosis.(c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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