Targeting TGF- fi/periostin signaling by sesamol ameliorates pulmonary fibrosis and improves lung function and survival

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disorder that severely impairs lung function, by increasing lung stiffness. Sesamol, a phe-nolic Phyto-molecule isolated from sesame seeds, possess a rich source of protein and is known to have extensive nutritional and health effects. Here we investigated the effect of sesamol on TGF-fi/periostin-induced fibroblast differentiation in in vitro and bleomycin-induced pulmonary fibrosis in an in vivo model. Our results demonstrated that activation of (DHLF, LL29, NHLF and A549) cells with TGF-fi, elevates the epithelial to mesenchymal transition, extra-cellular matrix, and collagen deposition and periostin signaling marker's expression, further treatment with sesamol attenuated these markers significantly. In addition, sesamol treatment improved the TGF-fi-induced contraction and migration of cells. Mechanistic studies showed that activation of IPF cells with periostin increased the TGF-fi signaling and treatment with sesamol significantly abrogated the periostin-induced TGF-fi activation and its downstream fi-brotic marker's expression. In in vivo, sesamol treatment attenuated the lung inflammation, infiltration of cells, wall thickening and the formation of fibrous bands significantly in BLM-induced fibrosis rats. Molecular studies revealed that sesamol treatment reduced the bleomycin-induced fibrotic, inflammatory, apoptotic marker's expression by modulating the TGF-fi/periostin crosstalk signaling in a dose-dependent manner. Further, treatment with sesamol dramat-ically improved lung function and decreased mortality. Our study first time reports the sesamol's inhibitory effects on periostin signalling. Collectively, our study demonstrated that periostin and TGF-fi seem to work in a positive-feedback loop, inducing the other, therefore, targeting TGF-fi/periostin signaling may provide a better therapeutic approach against IPF and other fibrotic disorders. (c) 2023 Elsevier Inc. All rights reserved.