Maiwei Yangfei decoction protects against pulmonary fibrosis by suppressing NLRP3 inflammasome-mediated pyroptosis of alveolar macrophage.

BACKGROUND

Pulmonary fibrosis (PF) is a progressive and irreversible pathological manifestation of fibrotic interstitial lung diseases, characterized by chronic inflammation, excessive extracellular matrix (ECM) deposition, and architectural distortion of lung parenchyma, ultimately leading to respiratory failure. Maiwei Yangfei Decoction (MWYF) has been clinically applied in PF treatment, and can effectively improve the lung function and life quality of PF patients. Nevertheless, the precise regulatory mechanisms underlying its anti-fibrotic effects require further investigation.

PURPOSE

To investigate MWYF's pharmacological action and potential mechanism against PF.

METHODS

Firstly, a PF mouse model was established by intratracheal nebulization of bleomycin (BLM). The effect of MWYF on PF was evaluated through micro-CT imaging and histopathological analysis. Subsequently, transcriptomics and proteomics were employed to investigate the crucial mechanism underlying the anti-fibrotic effects of MWYF. Immunofluorescence (IF), ELISA, TEM, SEM, Western blot (WB), and qPCR were then conducted to validate the inhibitory effects of MWYF on alveolar macrophages (AM) pyroptosis both in vivo and in vitro. Finally, the NLRP3 inhibitor (MCC950) was applied in MH-S cells to investigate the impact of MWYF on NLRP3 inflammasome.

RESULTS

MWYF exhibited significant efficacy against BLM-induced PF. Integrated transcriptomic and proteomic analyses suggested that NLRP3 inflammasome-mediated pyroptosis intrinsically participated in the anti-fibrotic effects of MWYF. Further in-vivo experiments confirmed that MWYF alleviated AM pyroptosis in lung tissues via modulating the assembly of the NLRP3 inflammasome. In vitro, MWYF inhibited LPS plus Nigericin-induced pyroptosis in MH-S cells, as well as primary mouse lung fibroblast (PMLF) proliferation, activation, and ECM secretion, by suppressing NLRP3 inflammasome activation.

CONCLUSION

This study illustrated that MWYF alleviated PF by inhibiting NLRP3 inflammasome-mediated AM pyroptosis by integrating multi-omics approaches, indicating that MWYF had promising clinical translational potential in PF therapy.