Hydroxysafflor yellow A ameliorates transforming growth factor-β1-triggered fibroblast activation via inactivation of the NF-κB/STAT3 pathway by suppressing ADAM17 expression.

Abstract

The abnormal proliferation and activation of fibroblasts have been implicated in idiopathic pulmonary fibrosis. Herein, the present research explored the impacts of the relationship between hydroxysafflor yellow A (HSYA) and a disintegrin and metalloproteinase 17 (ADAM17) on fibroblast activation, which can provide novel insight into the treatment and management of idiopathic pulmonary fibrosis. MRC-5 fibroblasts were firstly activated with TGF-β1, followed by measurement of ADAM17 expression through qRT-PCR and Western blot. Fibrosis-related gene and protein expression levels, cell viability, proliferation, migration, and fibroblast-to-myofibroblast transdifferentiation were determined by qRT-PCR and Western blot, MTS, EdU, Transwell, and immunofluorescence assays, respectively. Moreover, the regulatory relationships among HSYA, ADAM17, and the NF-κB/STAT3 pathway in MRC-5 cells were analyzed by bioinformatics analysis, qRT-PCR, and Western blot. The results show that HSYA treatment could diminish the fibrosis-related gene and protein expression patterns, proliferation, migration, and fibroblast-to-myofibroblast transdifferentiation in TGF-β1-stimulated MRC-5 cells. Moreover, HSYA could repress the TGF-β1-triggered ADAM17 up-regulation, thereby suppressing the NF-κB/STAT3 pathway. Furthermore, over-expression of ADAM17 negated the inhibitory effect of HSYA on fibroblast activation induced by TGF-β1. The findings revealed that HSYA blocked the NF-κB/STAT3 pathway activation by down-regulating ADAM17, thereby inhibiting TGF-β1-induced fibroblast activation.