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

Lingzhi Long; Xiaoqing Dai; Tingting Yao; Xiangyu Zhang; Guoliang Jiang; Xiaoyun Cheng; Mao Jiang; Yijun He; Zhangzhe Peng; Gaoyun Hu; Lijian Tao; Jie Meng

Biomedicine & Pharmacotherapy (Sep 2024)

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

Lingzhi Long,
Xiaoqing Dai,
Tingting Yao,
Xiangyu Zhang,
Guoliang Jiang,
Xiaoyun Cheng,
Mao Jiang,
Yijun He,
Zhangzhe Peng,
Gaoyun Hu,
Lijian Tao,
Jie Meng

Affiliations

Lingzhi Long: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Xiaoqing Dai: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Tingting Yao: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Xiangyu Zhang: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Guoliang Jiang: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Xiaoyun Cheng: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Mao Jiang: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Yijun He: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China
Zhangzhe Peng: Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China; Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China
Gaoyun Hu: Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China; Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China
Lijian Tao: Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China; Department of Nephrology, Xiangya Hospital, Central South University, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China
Jie Meng: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China; Corresponding author at: Department of Pulmonary and Critical Care Medicine, Third Xiangya Hospital, Central South University, Changsha 410013, China.

Journal volume & issue: Vol. 178
p. 117216

Abstract

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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 markers. Additionally, MFD treatment significantly suppressed the activation of fibroblasts and alveolar epithelial cells co-cultured with silica-exposed mouse macrophages. Ultimately, in the 28-day silica-exposed mouse models, MFD administration led to a substantial reduction in the severity of pulmonary fibrosis. Conclusion: MFD mitigates silica-induced pulmonary inflammation and fibrosis in mice by suppressing the TLR4-NF-κB/MAPK signaling pathway and reducing pyroptotic responses in macrophages. MFD could potentially emerge as a novel therapeutic agent for the treatment of silicosis.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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