Inflammation requires intensive metabolic support and modulation of the metabolic pathways might become a novel strategy to limit inflammatory injury. Recent studies have revealed the anti-inflammatory effects of the anti-diabetic reagent metformin, but the underlying mechanisms remain unclear. In the present study, the potential effects of metformin on endotoxemia-induced acute lung injury (ALI) and their relationship with the representative metabolic regulator, including AMPK, sirtuin 1 and mTOR, were investigated. The results indicated that treatment with metformin suppressed LPS-induced upregulation of IL-6 and TNF-α, alleviated pulmonary histological abnormalities, improved the survival rate of LPS-challenged mice. Treatment with metformin reversed LPS-induced decline of AMPK phosphorylation. Co-administration of the AMPK inhibitor compound C abolished the stimulatory effects of metformin on AMPK phosphorylation, the suppressive effects of metformin on IL-6 induction and pulmonary lesions. In addition, co-administration of the mTOR activator 3BDO but not the sirtuin 1 inhibitor EX-527 abolished the effects of metformin on IL-6 induction and pulmonary lesions. Finally, treatment with metformin suppressed LPS-induced p70S6K1 phosphorylation, which was abolished by the AMPK inhibitor. These data suggest that metformin might provide anti-inflammatory benefits in endotoxemia-induced inflammatory lung injury via restoring AMPK-dependent suppression of mTOR.

炎症需要强烈的代谢支持，而代谢途径的调节可能成为限制炎症损伤的新策略。最近的研究表明抗糖尿病药二甲双胍具有抗炎作用，但其潜在机制尚不清楚。在本研究中，研究了二甲双胍对内毒素血症引起的急性肺损伤（ALI）的潜在作用及其与代表性代谢调节剂（包括AMPK，sirtuin 1和mTOR）的关系。结果表明t二甲双胍治疗可抑制LPS诱导的IL-6和TNF-α上调，减轻肺组织异常，提高LPS攻击小鼠的存活率。二甲双胍治疗可逆转LPS诱导的AMPK磷酸化下降。AMPK抑制剂化合物C的共同给药消除了二甲双胍对AMPK磷酸化的刺激作用，二甲双胍对IL-6诱导和肺部病变的抑制作用。此外，mTOR激活剂3BDO而不是瑟土因1抑制剂EX-527的共同给药消除了二甲双胍对IL-6诱导和肺部病变的影响。最后，用二甲双胍治疗可抑制LPS诱导的p70S6K1磷酸化，该磷酸化被AMPK抑制剂消除。