Vistusertib improves pulmonary inflammation and fibrosis by modulating inflammatory/oxidative stress mediators via suppressing the mTOR signalling

IntroductionInflammation and oxidative stress are key factors in the development of pulmonary fibrosis (PF) by promoting the differentiation of fibroblasts through modulating various pathways including Wnt/beta-catenin, TGF-beta and mTOR signalling.Objective and methodsThis study aimed to evaluate the effects and elucidate the mechanisms of vistusertib (VSB) in treating pulmonary inflammation/fibrosis, specifically by targeting the mTOR pathway using various in vitro and in vivo models.ResultsLipopolysaccharide (LPS)-induced inflammation model in macrophages (RAW 264.7), epithelial (BEAS-2B) and endothelial (HMVEC-L) cells revealed that treatment with VSB significantly reduced the IL-6, TNF-alpha, CCL2, and CCL7 expression. TGF-beta induced differentiation was also significantly reduced upon VSB treatment in fibrotic cells (LL29 and DHLF). Further, bleomycin-induced inflammation and fibrosis models demonstrated that treatment with VSB significantly ameliorated the severe inflammation, and lung architectural distortion, by reducing the inflammatory markers expression/levels, inflammatory cells and oxidative stress indicators. Further, fibrosis model results exhibited that, VSB treatment significantly reduced the alpha-SMA, collagen and TGF-beta expressions, improved the lung architecture and restored lung functions.ConclusionOverall, this study uncovers the anti-inflammatory/anti-fibrotic effects of VSB by modulating the mTOR activation. Although VSB was tested for lung fibrosis, it can be tested for other fibrotic disorders to improve the patient's survival and quality of life.