Chemical Chaperone of Endoplasmic Reticulum Stress Inhibits Epithelial-Mesenchymal Transition Induced by TGF-[beta]1 in Airway Epithelium via the c-Src Pathway

Epithelial-mesenchymal transition (EMT) is a biological process that allows epithelial cells to assume a mesenchymal cell phenotype. EMT is considered as a therapeutic target for several persistent inflammatory airway diseases related to tissue remodeling. Herein, we investigated the role of endoplasmic reticulum (ER) stress and c-Src in TGF-[beta]1-induced EMT. A549 cells, primary nasal epithelial cells (PNECs), and inferior nasal turbinate organ cultures were exposed to 4- phenylbutylic acid (4PBA) or PP2 and then stimulated with TGF-[beta]1. We found that E-cadherin, vimentin, fibronectin, and [alpha]-SMA expression was increased in nasal polyps compared to inferior turbinates. TGF-[beta]1 increased the expression of EMT markers such as E-cadherin, fibronectin, vimentin, and [alpha]-SMA and ER stress markers (XBP-1s and GRP78), an effect that was blocked by PBA or PP2 treatment. 4-PBA and PP2 also blocked the effect of TGF-[beta]1 on migration of A549 cells and suppressed TGF-[beta]1-induced expression of EMT markers in PNECs and organ cultures of inferior turbinate. In conclusion, we demonstrated that 4PBA inhibits TGF-j31-induced EMT via the c-Src pathway in A549 cells, PNECs, and inferior turbinate organ cultures. These results suggest an important role for ER stress and a diverse role for TGF-[beta]1 in upper airway chronic inflammatory disease such as CRS.