Artesunate ameliorates lung fibrosis via inhibiting the Notch signaling pathway

Abstract

The present study aimed to determine the underlying molecular mechanism of the antifibrotic effect of artesunate in pulmonary fibrosis (PF). Primary lung fibroblasts were isolated from the lung tissues of rats, and treated with artesunate (8 µg/ml) and transforming growth factor (TGF)-β1 (5 ng/ml). For in vivo experiments, the rats were administered bleomycin intratracheally, followed by daily intraperitoneal artesunate injections for 27 days. Western blotting, and immunohistochemical and immunofluorescent staining were used to assess the expression of key components of the Notch signaling pathway, including α-smooth muscle actin (α-SMA) and type IV collagen. Artesunate (8 µg/ml) was identified to inhibit TGF-β1-induced α-SMA and collagen protein expression, and repress the Notch signaling pathway, in primary lung fibroblasts. Downregulation of α-SMA and collagen by artesunate was associated with inhibition of the Notch signaling pathway. The daily intraperitoneal injection of artesunate (1 mg/kg) in rats was determined to inhibit bleomycin-induced overexpression of α-SMA and type IV collagen proteins, and inhibit the Notch signaling pathway, in lung tissues. In conclusion, the results of the current study indicate that artesunate inhibits the TGF-β1-induced differentiation of rat primary lung fibroblasts into myofibroblasts and ameliorates bleomycin-induced PF. In addition, the results of the present study suggest that the underlying molecular mechanism for these effects of artesunate is repression of the Notch signaling pathway.

High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation

“…These data are also in line with multiple lines of evidence, supporting an antifibrotic role of the Notch pathway (80,81). Notch pathway components were found upregulated in models of cardiac, lung, skin, and liver fibrosis and chemical inhibition of the pathway invariably reduced the fibrotic signature, improving the outcome of the disease (82)(83)(84)(85).…”

Bufei Qingyu Granules Inhibit the Development of Systemic Sclerosis via Notch-1/Jagged-2 Signaling Pathway

“…Additionally, fibrosis could be ameliorated by inhibition of Notch signaling pathway, applying a γ -secretase inhibitor (DAPT) or overexpression of a Notch-1 antisense construct [34, 35], which was in agreement with Kavian et al's findings [36]. It was reported that Notch deficiency resulted in a crucial inhibitory effect on the response to BLM-induced dermal fibrosis and lung fibrosis [37]. To our knowledge, core elements of this signaling pathway consists of four Notch transmembrane receptors and five transmembrane ligands in mammals named as follows: Notch 1-4, three Delta-like proteins (DLL1, DLL3, and DLL4), and two Jagged proteins (Jag 1, 2).…”

Idiopathic Pulmonary Fibrosis and Lung Cancer: Mechanisms and Molecular Targets

“…Finally, rovalpituzumab treatment, although not tested for NSCLC, is currently approved for SCLC, and it could also have potential in the treatment of IPF and LC-IPF, since it interferes with the Notch signalling pathway. In fact, it has been observed that artesunate ameliorates lung fibrosis via inhibiting the Notch signaling pathway in a rat bleomycin model [261].…”