Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury
Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury
复制标题
肺上皮细胞中 MTOR 的激活促进 LPS 诱导的急性肺损伤
DOI：
10.1080/15548627.2016.1230584
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Shen, Hua-Hao
中科院分区：
文献类型：
--
作者：
Hu, Yue;Lou, Jian;Shen, Hua-Hao
摘要MTOR(雷帕霉素的机械性靶标[丝氨酸/苏氨酸激酶])在许多重要的细胞过程中发挥着重要作用，包括代谢、增殖和巨自噬/自噬诱导，并与越来越多的增殖性和代谢性疾病有关。MTOR和自噬都被认为与肺部疾病有关，然而，对于MTOR和自噬在急性肺损伤(ALI)中的作用知之甚少。在本研究中，我们观察到脂多糖刺激诱导微管相关蛋白1LC3B/LC3B(微管相关蛋白1轻链3β)-II在小鼠肺上皮和人支气管上皮细胞中的表达。HBE细胞中MTOR的激活是由Toll样受体4(Toll-like Receptor 4)信号介导的。MTOR的基因敲除或自噬相关蛋白的过度表达显著减弱，而抑制自噬则通过NFKB信号进一步增强内毒素诱导的HBE细胞中IL-6(IL-6)和IL-8的表达。在支气管或肺泡上皮细胞中特异性敲除mTOR的小鼠表现出显著的减轻呼吸道炎症、屏障破坏和肺水肿，并延长了对脂多糖暴露的生存时间。综上所述，我们的结果表明，上皮中MTOR的激活促进了内毒素诱导的ALI，可能是通过下调自噬和随后激活NFKB来实现的。因此，抑制肺上皮细胞MTOR可能是预防某些细菌所致ALI的一种新的治疗策略。
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.