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

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disorder that severely impairs lung function, by increasing lung stiffness. Sesamol, a phenolic 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-β/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-β, elevates the epithelial to mesenchymal transition, extracellular 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-β-induced contraction and migration of cells. Mechanistic studies showed that activation of IPF cells with periostin increased the TGF-β signaling and treatment with sesamol significantly abrogated the periostin-induced TGF-β activation and its downstream fibrotic 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-β/periostin crosstalk signaling in a dose-dependent manner. Further, treatment with sesamol dramatically 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-β seem to work in a positive-feedback loop, inducing the other, therefore, targeting TGF-β/periostin signaling may provide a better therapeutic approach against IPF and other fibrotic disorders.

Keywords: Collagen; Interleukins; Neutrophil-elastase; Periostin; Phytochemicals; Pulmonary-fibrosis.