Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury

Abstract

MTOR (mechanistic target of rapamycin [serine/threonine kinase]) plays a crucial role in many major cellular processes including metabolism, proliferation and macroautophagy/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 lipopolysaccharide (LPS) stimulation induced MTOR phosphorylation and decreased the expression of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β)-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 TLR4 (toll-like receptor 4) signaling. Genetic knockdown of MTOR or overexpression of autophagy-related proteins significantly attenuated, whereas inhibition of autophagy further augmented, LPS-induced expression of IL6 (interleukin 6) 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 downregulation of autophagy and the 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.

Curcumin Inhibits Heat-Induced Apoptosis by Suppressing NADPH Oxidase 2 and Activating the Akt/mTOR Signaling Pathway in Bronchial Epithelial Cells

“…Of note, S6K1, S6 and 4E-BP1 are downstream of mTOR, regulating cell motility. S6K1 and S6 have been considered to regulate apoptosis, the cell cycle and metabolism [32]. 4EBP1 plays an important role in protein synthesis, cell growth and cell proliferation [33].…”

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

“…The molecular mechanisms responsible for the mTOR‐dependent activation of NOX and NF‐κB in response to BCAA are unknown and this is a limitation of our study. However, other authors have also found a role for mTOR in oxidative stress generation40, 41 or NF‐κB activation in response to different stimuli or pathological conditions 42, 43. Besides mTORC1, BCAA trigger several signalling responses via the activation of AMPK, which plays a role in cellular energy homoeostasis.…”

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

“…Accordingly, rapamycin treatment partially protects mice from IPF caused by bleomycin 241 or radiation 244 , as well as from hypoxia-induced PAH 245 . Similarly, the intranasal delivery of a Becn1 -coding lentivirus successfully restores autophagy and limits inflammation in Cftr F508Δ mice (a model of cystic fibrosis) 243 , as does the genetic inactivation of Rptor or Mtor in mouse models of hyperoxia-induced or lipopolysaccharide-induced acute lung injury 246,247 . Moreover, Map1lc3b −/− mice exhibit aggravated PAH upon chronic hypoxia 242 .…”