Cellular senescence and EMT crosstalk in bleomycin-induced pathogenesis of pulmonary fibrosis-an in vitro analysis.

With poor prognosis and aberrant lung remodeling, pulmonary fibrosis exhibits worldwide prevalence accompanied by an increase in burden in terms of hospitalization and death. Apart from genetic and non-genetic factors, fibrosis occurs as a side effect of bleomycin antineoplastic activity. Elucidating the cellular and molecular mechanism could help in the development of effective anti-fibrotic treatment strategies. In the present study, we investigated the underlying mechanism behind bleomycin-induced fibrosis using human alveolar epithelial cells (A549 cells). On the basis of the experimental observation, it was demonstrated that with transforming growth factor-β (TGF-β) as a central mediator of fibrosis progression, a cross-talk between epithelial-mesenchymal transition (EMT) and senescence upon bleomycin treatment occurs. This results in the advancement of this serious fibrotic condition. Fibrosis was initiated through integrin activation and imbalance in the redox state (NOX expression) of the cell. It progressed along the TGF-β-mediated non-canonical pathway (via ERK phosphorylation) followed by the upregulation of α-smooth muscle actin and collagen synthesis. Additionally, in this process, the loss of the epithelial marker E-cadherin was observed. Furthermore, the expressions of senescence markers, such as p21 and p53, were upregulated upon bleomycin treatment, thereby intensifying the fibrotic condition. Accordingly, the molecular pathway mediating the bleomycin-induced fibrosis was explored in the current study.