Salvinorin A alleviates Idiopathic pulmonary fibrosis by inhibiting M2 macrophage polarization and macrophage-to-myofibroblast transition

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with limited treatment options. Macrophages, as the primary immune cells in the lungs, play a key role in the progression of pulmonary fibrosis. Salvinorin A (SA), a naturally occurring non-nitrogenous diterpenoid, exhibits anti-inflammatory and anti-neuropathic pain effects in various models. However, whether SA alleviates IPF by modulating macrophage function remains unclear. Methods: This study aimed to investigate the therapeutic effects and mechanisms of SA on bleomycin-induced pulmonary fibrosis in mice. A bleomycin-induced IPF mouse model was established, and SA was administered via intraperitoneal injection starting from day 7 post-modeling. The study further explored the effects of SA on M2 macrophage polarization and macrophage-to-myofibroblast transition (MMT) both in vivo and in vitro. Results: SA treatment significantly alleviated the degree of pulmonary fibrosis and inflammatory response, improved lung tissue pathological structure, and reduced extracellular matrix deposition and the release of related inflammatory cytokines. Mechanistic studies revealed that SA effectively inhibited M2 macrophage polarization both in vivo and in vitro, as evidenced by the downregulation of marker molecules such as CD206, Arg1, Fizz1, and YM1. Additionally, SA also inhibited MMT, specifically manifested as a significant decrease in the proportion of α-SMA⁺CD68⁺ double-positive cells. Conclusion: This study reveals that SA can effectively alleviate the progression of pulmonary fibrosis by dually inhibiting M2 macrophage polarization and the MMT process, providing important experimental evidence for SA as a potential therapeutic agent against pulmonary fibrosis.