Bleomycin induces epithelial-to-mesenchymal transition via bFGF/PI3K/ESRP1 signaling in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal and chronic disease with a high rate of infection and mortality; however, its etiology and pathogenesis remain unclear. Studies have revealed that epithelial-mesenchymal transition (EMT) is a crucial cellular event in IPF. Here, we identified that the pulmonary fibrosis inducer bleomycin simultaneously increased the expression of bFGF and TGF-β1 and inhibited epithelial-specific regulatory protein (ESRP1) expression in vivo and in vitro. In addition, in vitro experiments showed that bFGF and TGF-β1 down-regulated the expression of ESRP1 and that silencing ESRP1 promoted EMT in A549 cells. Notably, we determined that bFGF activates PI3K/Akt signaling, and treatment with the PI3K/Akt inhibitor LY294002 inhibited bleomycin-induced cell morphology changes and EMT. In addition, the effects of LY294002 on bleomycin-induced EMT were inhibited by ESRP1 silencing in A549 cells. Taken together, these findings suggest that bleomycin induced EMT through down-regulating ESRP1 by simultaneously increasing bFGF and TGF-β1 in pulmonary fibrosis. Additionally, our findings indicated that bFGF inhibits ESRP1 by activating PI3K/Akt signaling.

Thal protects against paraquat‐induced lung injury through a microRNA‐141/HDAC6/IκBα‐NF‐κB axis in rat and cell models

“…40 Likewise, the anti-inflammatory effect of thalidomide was also found in influenza A (H1N1) virus-induced pulmonary injury in mice by reducing the secretion of pro-inflammatory cytokines. 41 In addition, bGFG is the mostly studied fibrosis-related factor, 42,43 and PQ has been reported to enhance bGFG expression and promote fibrosis in rat lungs, 44 while thalidomide has been reported to inhibit bFGF expression in rats, 45 which was partially in line with our findings. Moreover, considering the teratogenicity 9 and potential side-effects of thalidomide, specifically, rats and cells were treated with thalidomide alone, and it was found that alone administration of thalidomide did not affect the lungs and cells.…”

Role of CXCL16 in BLM-induced epithelial–mesenchymal transition in human A549 cells

“…Here, a well-validated model of EMT in the A549 human alveolar cell line was used to study the mechanism of pulmonary fibrosis, for which a suite of morphological, phenotypic and functional markers and outcomes have been well characterized [31][32][33]. BLM is widely used as an inducer of pulmonary fibrosis in animal models [34], and similar effects were validated in vitro experiments, and EMT characteristics were detected in BLM treated A549 cells [35,36]. Our research discovered that CXCL16 and its receptor CXCR6 were upregulated in BLM-induced EMT in the human A549 cells.…”

Fatty acid nitroalkene reversal of established lung fibrosis

“…Epithelial cell injury is central to the pathogenesis of IPF [ 126 ], and is an early manifestation of bleomycin-induced inflammation [ 47 ]. DNA damage in bleomycin induced injury, as multiple risk factors for IPF, leads to loss of epithelial cell numbers and functions [ [126] , [127] , [128] ]. In IPF, epithelial cells show impaired surfactant protein production, E-cadherin and cytokeratin expression, along with other functional impairments.…”