Abstract
Aberrant activation of TGF-β1 is frequently encountered and promotes epithelial-mesenchymal transition (EMT) and fibroblast activation in pulmonary fibrosis. The present study investigated whether emodin mediates its effect via suppressing TGF-β1-induced EMT and fibroblast activation in bleomycin (BLM)-induced pulmonary fibrosis in rats. Here, we found that emodin induced apoptosis and inhibited cellular proliferation, migration and differentiation in TGF-β1-stimulated human embryonic lung fibroblasts (HELFs). Emodin suppressed TGF-β1-induced EMT in a dose- and time-dependent manner in alveolar epithelial A549 cells. Emodin also inhibited TGF-β1-induced Smad2, Smad3 and Erk1/2 activation, suggesting that Smad2/3 and Erk1/2 inactivation mediated the emodin-induced effects on TGF-β1-induced EMT. Additionally, we provided in vivo evidence suggesting that emodin apparently alleviated BLM-induced pulmonary fibrosis and improved pulmonary function by inhibiting TGF-β1 signaling and subsequently repressing EMT, fibroblast activation and extracellular matrix (ECM) deposition. Taken together, our data suggest that emodin mediates its effects mainly via inhibition of EMT and fibroblast activation and thus has a potential for the treatment of pulmonary fibrosis.
Highlights
Transforming growth factor (TGF)-β1, a key fibrogenic cytokine, regulates diverse cellular functions including migration, proliferation, differentiation, and apoptosis[10,11]
We found that emodin induced apoptosis and inhibited cell proliferation, migration and differentiation in TGF-β1-stimulated human embryonic lungfibroblasts (HELFs)
We present in vivo evidence showing that emodin significantly repressed TGF-β1 signaling, EMT, fibroblast activation and eventual ECM deposition in the BLM-treated lungs indicating potential therapeutic efficacy of emodin in pulmonary fibrosis
Summary
Transforming growth factor (TGF)-β1 , a key fibrogenic cytokine, regulates diverse cellular functions including migration, proliferation, differentiation, and apoptosis[10,11] It is aberrantly expressed in the lungs of patients suffering from IPF12. In addition to triggering the differentiation of fibroblasts into myofibroblasts and maintenance of contractile phenotype, it induces EMT in AECs and plays a critical role in EMT-mediated organ fibrosis via canonical and non-canonical Smad signaling[5,11,13]. Both the pathways suppress the expression of E-cadherin by zinc-finger transcription factors such as Slug, ZEB and Snail[14]. We present in vivo evidence showing that emodin significantly repressed TGF-β1 signaling, EMT, fibroblast activation and eventual ECM deposition in the BLM-treated lungs indicating potential therapeutic efficacy of emodin in pulmonary fibrosis
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