Eupalinolide A attenuates bleomycin-induced pulmonary fibrosis by inhibiting lung fibroblast transition

This work aimed to investigate the effects of eupalinolide A on bleomycin-induced pulmonary fibrosis and the possible underlying mechanism. We found that in vitro, the antifibrotic activity of eupalinolide A was better than that of eupalinolide G and eupalinolide I and that it was also superior to that of ginkgolide A, ginkgolide B, ginkgolide C, and bilobalide. Eupalinolide A significantly suppressed lung fibroblast transition and decreased the production of extracellular matrix (ECM). Mechanistically, eupalinolide A reduced serum response factor (SRF) levels. Knockdown of SRF inhibited lung fibroblast transition, confirming the effect of eupalinolide A. Moreover, eupalinolide A significantly reduced the level of phosphorylated extracellular regulated protein kinase (ERK), and knockdown of ERK significantly suppressed the transforming growth factor β1 (TGF-β1)-induced increase in SRF levels and lung fibroblast transition. Eupalinolide A significantly reduced the level of phosphorylated mitogen-activated protein kinase kinase (MEK), and genetic and pharmacological inhibition of MEK significantly decreased the levels of phosphorylated ERK, the levels of SRF and the transition of lung fibroblasts. In vivo, eupalinolide A reduced ECM deposition, and inhibited lung fibroblast transition. Additionally, eupalinolide A decreased the levels of phosphorylated MEK/ERK and the level of SRF in mouse lung tissues. Together, this study was the first evidence to demonstrate that eupalinolide A attenuates lung fibrosis by inhibiting the abnormal transition of lung fibroblasts and that the underlying mechanism is related to MEK/ERK/SRF signaling pathway inhibition. These findings provide evidence for the discovery of lead compounds with novel structures for use in treating chemical therapy-induced pulmonary fibrosis.