Mechanisms Of MTOR And Autophagy In LPS-induced Acute Lung Injury

Backgrounds:The mechanistic target of rapamycin (mTOR) play a crucial role in response to many major cellular processes including cellular metabolism, proliferation and autophagy induction, and is also implicated in a growing number of proliferative and metabolic diseases. Both mTOR and autophagy is suggested to be involved in the regulation of acute lung injury (ALI). However, little is known about the role of mTOR and autophagy in pulmonary epithelium in the context of ALI.Objective:To examine the expression of mTOR-autophagy signaling pathways and associated inflammatory cytokines, pulmonary epithelial cells (HBE) were exposed to lipopolysaccharide (LPS) in vitro. Alveoli and airway epithelium-specific mTOR knockout mice were given LPS intratracheally, and 24h later the mice were sacrificed for analyzing of the severity of integrity of lung barrier and the extent of inflammation.Methods:To examine the expression of mTOR-autophagy signaling pathways and associated inflammatory cytokines, pulmonary epithelial cells (HBE) were exposed to lipopolysaccharide (LPS) in vitro. Alveoli and airway epithelium-specific mTOR knockout mice were given LPS intratracheally, and 24h later the mice were sacrificed for analyzing of the severity of integrity of lung barrier and the extent of inflammation.Results:In the present study, we observed that LPS stimulation induced mTOR phosphorylation and decreased the expression of LC3B-II, a hallmark of autophagy, in human bronchial epithelial (HBE) cells and in mouse lung epithelium. 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 (IL-6) and interleukin-8 (IL-8) through nuclear factor-KB (NF-κB) signaling in HBE cells. Mice with specific knockdown of mTOR in bronchial or alveolar epithelial cells exhibited markedly attenuated airway inflammation, barrier disruption, and lung edema, while displayed prolonged survival in response to LPS exposure.Conclusion: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 NF-κB. Thus, inhibition of mTOR in pulmonary epithelial cells may represent a novel therapeutic strategy for preventing LPS-induced ALI.