Dehydrocostus lactone inhibits BLM-induced pulmonary fibrosis and inflammation in mice via the JNK and p38 MAPK-mediated NF-κB signaling pathways

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible inflammatory disease with a high mortality rate and limited therapeutic options. This study explored the potential role and mechanisms of Dehydrocostus lactone (DHL) in the inflammatory and fibrotic responses in a bleomycin (BLM) induced model. Treatment with DHL significantly reduced pathological injury and fibrosis, the secretion of BLM-induced pro-fibrotic mediators TGF-beta and alpha -SMA, and components of the extracellular matrix (fibronectin). Additionally, in the early stages of inflammation, DHL administration inhibited the infiltration of inflammatory cells and downregulated the expression of TGF-beta, TNF-alpha, and IL-6, indicating that DHL treatment effectively alleviated BLM-induced pulmonary fibrosis and inflammation in a dose-dependent manner. Furthermore, BLM induced the production of IL-33 in vivo, which initiated and progressed pulmonary fibrosis by activating macrophages and enhancing the production of IL-13 and TGF-beta. In contrast, a significant decrease in the expression of IL-33 after DHL treatment in vitro showed that DHL strongly reduced IL-13 and TGF-beta. Regarding the mechanism, BLM-induced phosphorylation of JNK, p38 MAPK, and NF-kappa B were significantly reduced after DHL treatment, which further led to the down-regulation of IL-33 expression, thereby decreasing IL-13 and TGF-beta. Collectively, our data suggested that DHL could exert its anti-fibrosis effect via inhibiting the early inflammatory response by downregulating the JNK/p38 MAPK-mediated NF-kappa B signaling pathway to suppress macrophage activation. Therefore, DHL has therapeutic potential for pulmonary fibrosis.

Automated summary

DHL treatment effectively alleviated BLM-induced pulmonary fibrosis and inflammation by reducing pro-fibrotic mediators, inhibiting inflammatory cell infiltration, and downregulating IL-33 expression. The mechanism involved the JNK/p38 MAPK-mediated NF-kappa B signaling pathway to suppress macrophage activation and decrease IL-13 and TGF-beta levels.