LATE-BREAKING ABSTRACT: Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury

Mechanistic target of rapamycin (MTOR) plays a crucial role in many major cellular processes includingmetabolism, proliferation and autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both MTOR and autophagy have been suggested to be involved in lung disorders, however, little is known about the role of MTOR and autophagy in pulmonary epithelium in the context of acute lung injury (ALI).In the present study, we observed that LPS stimulation induced MTORphosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3β)-II, a hallmark of autophagy, in mouse lung epithelium and in human bronchial epithelial (HBE) cells. The activation of MTOR in HBE cells was mediated by the toll-like receptor 4 signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, while inhibition of autophagy further augmented LPS-induced expression of interleukin 6 (IL6) and IL8, through NFKB signaling in HBE cells. Mice with specific knockdown of Mtor in bronchial or alveolar epithelial cells exhibited significantly attenuated airway inflammation, barrier disruption, and lung edema, and displayed prolonged survival in response to LPS exposure.Taken together, our results demonstrate that activation of MTOR in the epithelium promotes LPS-induced ALI, likely through down-regulation of autophagy and its subsequent activation of NFKB. Thus,inhibition of MTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing ALI induced by certain bacteria.