Lycorine Ameliorates Bleomycin-induced Pulmonary Fibrosis Via Inhibiting The Activation Of NLRP3 Inflammasome

Idiopathic pulmonary fibrosis(IPF)is an irreversible and chronic lung disease with limited therapeutic strategies.Lycorine(LYC)is an alkaloid compound isolated from Amaryllidaceae family plants.Previous studies have shown that LYC exhibits effective antiinflammatory,antiviral and anti-tumor activities.However,the effect of LYC on IPF remains unclear.In this study,bleomycin(BLM)-induced IPF mouse model in vivo and cell experiments in vitro were conducted to investigate the effects of LYC on the regulation of IPF at the whole-cell-molecular level.Our results showed that the intraperitoneal injection of LYC could effectively alleviate the pulmonary fibrosis injury induced by BLM in mice,inhibit the release of cytokines and the activation of caspase-1 in the inflammatory stage of early pulmonary fibrosis.In addition,LYC could significantly inhibit the activation of NACHT,LRR and PYD domains-containing protein 3(NLRP3)inflammasome and pyroptosis in macrophages induced by LPS/Nigericin or LPS/ATP.Finally,we also found that LYC could interfere with the interaction of NLRP3 with apoptosis-associated specklike protein containing a CARD protein(ASC)by targeting on the pyrin domain(PYD)of ASC molecules so as to inhibit the activation of NLRP3 inflammasome.To sum up,our study showed that LYC could inhibit the activation of inflammasome and pyrotosis by intervening the interaction between ASC and NLRP3,and play a regulatory role in BLMinduced pulmonary fibrosis.Our study provides a favorable theoretical basis for the development of drugs to treat IPF with LYC as a promising compound.