Mefunidone alleviates silica-induced inflammation and fibrosis by inhibiting the TLR4-NF-κB/MAPK pathway and attenuating pyroptosis in murine macrophages

作者：Lingzhi Long, Xiao‐Qing Dai, Tingting Yao, Xiangyu Zhang, Guoliang Jiang, Xiaoyun Cheng, Mao Jiang, Yijun He, Zhangzhe Peng, Gaoyun Hu, Lijian Tao, Jie Meng · 发表于：Biomedicine & Pharmacotherapy · 年份：2024 · DOI：10.1016/j.biopha.2024.117216 · 被引用次数：29 · 研究领域：Inflammasome and immune disorders、Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis、Pediatric health and respiratory diseases

AIMS: Silicosis is the most common and severe type of pneumoconiosis, imposing a substantial disease burden and economic loss on patients and society. The pathogenesis and key targets of silicosis are not yet clear, and there are currently no effective treatments available. Therefore, we conducted research on mefunidone (MFD), a novel antifibrotic drug, to explore its efficacy and mechanism of action in murine silicosis. METHODS: Acute 7-day and chronic 28-day silicosis models were constructed in C57BL/6J mice by the intratracheal instillation of silica and subsequently treated with MFD to assess its therapeutic potential. The effects of MFD on silica-induced inflammation, pyroptosis, and fibrosis were further investigated using immortalized mouse bone marrow-derived macrophages (iBMDMs). RESULTS: In the 7-day silica-exposed mouse models, MFD treatment significantly alleviated pulmonary inflammation and notably reduced macrophage infiltration into the lung tissue. RNA-sequencing analysis of silica-induced iBMDMs followed by gene set enrichment analysis revealed that MFD profoundly influenced cytokine-cytokine receptor interactions, chemokine signaling, and the toll-like receptor signaling pathways. MFD treatment also markedly reduced the secretion of inflammatory cytokines and chemokines from silica-exposed iBMDMs. Moreover, MFD effectively downregulated the activation of the TLR4-NF-κB/MAPK signaling pathway induced by silica and mitigated the upregulation of pyroptosis mark...