mTOR mediates airway epithelial E-cadherin disruption in toluene diisocyanate-induced asthma.

E-cadherin is a critical adheren junctional protein for maintaining airway epithelial integrity. Downregulation of E-cadherin is commonly seen in asthma. Mammalian target of rapamycin (mTOR), a central regulator of metabolism, is implicated in asthma pathogenesis. This study was aimed to elucidate the role of mTOR signaling pathway on airway epithelial E-cadherin dysfunction in toluene diisocyanate (TDI)-induced asthma. Male BALB/c mice and in vitro cultured airway epithelial cell line BEAS-2B were exposed to TDI for modeling, and treated with rapamycin, an inhibitor of the mTOR signaling. We observed increased phosphorylation of mTOR and its downstream molecule p70s6k in TDI-exposed mice and cultured epithelia, indicating activation of mTOR signaling. In vivo, treatment with rapamycin dramatically alleviated TDI-induced airway hyperreactivity, decreased airway neutrophilia and eosinophilia, and suppressed the release of IL-4, IL-5 and IL-17 in the bronchoalveolar lavage fluid (BALF), suggesting a central role for mTOR in the development of TDI-induced asthma. Moreover, the TDI-induced downregulated E-cadherin expression in the lung was also significantly recovered by rapamycin, accompanied by less production of soluble E-cadherin (sE-cadherin), which is a marker of E-cadherin disruption and epithelial injury. Similar results were observed in cultured airway epithelial cells. Taken together, our data demonstrated that mTOR mediates airway epithelial E-cadherin disruption in TDI-induced asthma.