Salvinorin A Alleviates Pulmonary Fibrosis by Inhibiting M2 Macrophage Polarization and MMT

Pulmonary fibrosis (PF) is a progressive, often fatal interstitial lung disease with severely limited treatment options. Current antifibrotic therapies can slow progression but do not reverse the irreversible scarring, highlighting a critical unmet need. Macrophages, as key immune cells in the lung, are central orchestrators of the fibrotic cascade, with M2 macrophage polarization and subsequent macrophage-to-myofibroblast transition (MMT) playing crucial roles in disease progression. Understanding these cellular mechanisms offers promising targets for novel therapeutic interventions.

Researchers investigated the therapeutic effects of Salvinorin A (SA) on bleomycin-induced pulmonary fibrosis in mice. A bleomycin-induced PF model was established, with SA administered via intraperitoneal injection starting from day 7 post-modeling. The study then explored SA's impact on M2 macrophage polarization and macrophage-to-myofibroblast transition (MMT) using both in vivo mouse models and in vitro cell culture systems. Primary endpoints included histological assessment of fibrosis, inflammatory markers, extracellular matrix deposition, and specific macrophage phenotypic markers.

Salvinorin A treatment significantly alleviated the degree of pulmonary fibrosis and inflammatory response in mice. It improved lung tissue pathological structure and reduced extracellular matrix deposition, along with the release of related inflammatory cytokines. Mechanistically, SA effectively inhibited M2 macrophage polarization both in vivo and in vitro, evidenced by the downregulation of key marker molecules such as CD206, Arg1, Fizz1, and YM1. This dual action suggests a comprehensive antifibrotic effect. Additionally, SA also inhibited macrophage-to-myofibroblast transition (MMT), specifically manifested as a significant decrease in the proportion of α-SMA⁺CD68⁺ double-positive cells, indicating reduced myofibroblast formation from macrophages. This dual inhibition of M2 polarization and MMT represents a novel pathway for therapeutic intervention.

Salvinorin A significantly reduced extracellular matrix deposition and inflammatory cytokine release, while also downregulating M2 macrophage markers CD206, Arg1, Fizz1, and YM1 both in vivo and in vitro.