Cepharanthine alleviates lipopolysaccharide-induced acute lung injury through modulating macrophage polarization

Acute lung injury (ALI) is a common, severe respiratory disorder frequently related to acute lung inflammation. As crucial immunoregulatory cells, macrophages critically influence the pathological trajectory of ALI, with their functional states serving as predictive biomarkers for both lesion severity and patient recovery trajectories. Cepharanthine (CEP), a natural bisbenzylisoquinoline (BBIQ) alkaloid, was shown to have substantial anti-inflammatory properties. However, whether CEP can alleviate ALI by regulating macrophage polarization needs to be clarified. Therefore, the therapeutic effect of CEP in ALI was explored via H&E staining, enzyme-linked immunosorbent assays (ELISAs), immunofluorescence, and western blot. In vivo, experimental data demonstrated that CEP intervention significantly ameliorated mouse pathological alterations. Specifically, the secretion levels of pro-inflammatory cytokines IL-6 and TNF-α were dose-dependently downregulated, while the expression of the anti-inflammatory mediator IL-10 exhibited a significant upregulation trend. Immunofluorescence staining revealed that CEP suppressed lipopolysaccharide (LPS)-induced M1 macrophage polarization and increased M2 macrophage polarization. Moreover, western blot results showed that CEP inhibited TLR4/MAPK signaling pathway activation but increased AMPK phosphorylation and Nrf2/HO-1 expression. Experimental findings from in vitro studies aligned with observations corresponding to in vivo models. In summary, CEP can regulate macrophage polarization to protect against LPS-induced ALI by interfering with TLR4/MAPK signaling and activating the AMPK/Nrf2 pathway.