Paeoniflorin mitigates MMP-12 inflammation in silicosis via Yang-Yin-Qing-Fei Decoction in murine models

Tian Li; Na Mao; Zihao Xie; Jianing Wang; Fuyu Jin; Yaqian Li; Shupeng Liu; Wenchen Cai; Xuemin Gao; Zhongqiu Wei; Fang Yang; Hong Xu; Heliang Liu; Haibo Zhang; Dingjie Xu

doi:10.1016/j.phymed.2024.155616

Paeoniflorin mitigates MMP-12 inflammation in silicosis via Yang-Yin-Qing-Fei Decoction in murine models

Phytomedicine. 2024 Apr 19:129:155616. doi: 10.1016/j.phymed.2024.155616. Online ahead of print.

Authors

Tian Li¹, Na Mao¹, Zihao Xie¹, Jianing Wang², Fuyu Jin¹, Yaqian Li¹, Shupeng Liu¹, Wenchen Cai¹, Xuemin Gao³, Zhongqiu Wei¹, Fang Yang¹, Hong Xu⁴, Heliang Liu⁵, Haibo Zhang⁶, Dingjie Xu⁷

Affiliations

¹ School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China.
² College of traditional Chinese medicine, North China University of Science and Technology, Tangshan, Hebei Province 063210, China.
³ School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China; National Health Commission (NHC) Key Laboratory of Pneumoconiosis, Taiyuan 030001, Shanxi province, China.
⁴ School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China; National Health Commission (NHC) Key Laboratory of Pneumoconiosis, Taiyuan 030001, Shanxi province, China; Health Science Center, North China University of Science and Technology, Tangshan, Hebei 063210, China.
⁵ School of Public Health, Hebei Key Laboratory for Organ Fibrosis Research, North China University of Science and Technology, Tangshan, China. Electronic address: liuheliang@ncst.edu.cn.
⁶ Department of Anesthesiology and Pain Medicine, Department of Physiology, Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada; The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada. Electronic address: Haibo.Zhang@unityhealth.to.
⁷ College of traditional Chinese medicine, North China University of Science and Technology, Tangshan, Hebei Province 063210, China. Electronic address: xudingjie@ncst.edu.cn.

PMID: 38669965
DOI: 10.1016/j.phymed.2024.155616

Abstract

Background: Silicosis presents a significant clinical challenges and economic burdens, with Traditional Chinese Medicine (TCM) emerging as a potential therapeutic avenue. However, the precise effects and mechanisms of TCM in treating silicosis remain uncertain and subject to debate.

Objective: The study aims to elucidate the therapeutic role and mechanisms of the Yang-Yin-Qing-Fei Decoction (YYQFD) and its key component, paeoniflorin, in silicosis using a murine model.

Methods: Silicotic mice were treated with YYQFD, pirfenidone (PFD), or paeoniflorin. RAW264.7 cells and mouse lung fibroblasts (MLF) were stimulated with silica, matrix metalloproteinase-12 (MMP-12), or TGF-β1, followed by treatment with paeoniflorin, PFD, or relevant inhibitors. YYQFD constituents were characterized using High-Performance Liquid Chromatography (HPLC). Lung fibrosis severity was assessed via histopathological examination, micro-CT imaging, lung functions, and Western blot analysis. Transcriptome sequencing and bioinformatics analysis were employed to delineate the gene expression profile and target genes modulated by YYQFD in silicosis.

Results: Treatment with YYQFD ameliorated silica-induced lung fibrosis. Transcriptome sequencing identified MMP-12 as a potential common target of YYQFD and PFD. Additionally, a potential pro-inflammatory role of MMP-12, regulated by silica-induced TLR4 signaling pathways, was revealed. Paeoniflorin, one of the most distinctive compounds in YYQFD, attenuated silica-induced MMP-12 increase and its derived inflammatory factors in macrophages through a direct binding effect. Notably, paeoniflorin treatment exerted anti-fibrotic effects by inhibiting MMP-12-derived inflammatory factors and TGF-β1-induced myofibroblast differentiation in silica-exposed mice.

Conclusions: This study underscores paeoniflorin as one of the most principal bioactive compounds in YYQFD, highlighting its capacity to attenuate lung inflammation driven by macrophage-derived MMP-12 and reduce lung fibrosis both in vivo and in vitro.

Keywords: Inflammation; Silicosis; Traditional Chinese medicine; Yang-Yin-Qing-Fei Decoction.