AMP-activated protein kinase reduces inflammatory responses and cellular senescence in pulmonary emphysema

被引:76
作者
Cheng, Xiao-Yu [1 ]
Li, Yang-Yang [1 ]
Huang, Cheng [1 ]
Li, Jun [1 ]
Yao, Hong-Wei [1 ]
机构
[1] Anhui Med Univ, Sch Pharm, Hefei, Peoples R China
关键词
cigarette smoke; AMPK; SIRT3; mitochondrial dysfunction; COPD; MITOCHONDRIAL OXIDATIVE STRESS; ELASTASE-INDUCED EMPHYSEMA; ANIMAL-MODELS; SIGNALING PATHWAY; AGING PHENOTYPES; LUNG-DISEASE; KLOTHO MICE; COPD; SUSCEPTIBILITY; PATHOGENESIS;
D O I
10.18632/oncotarget.15116
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Current drug therapy fails to reduce lung destruction of chronic obstructive pulmonary disease (COPD). AMP-activated protein kinase (AMPK) has emerged as an important integrator of signals that control energy balance and lipid metabolism. However, there are no studies regarding the role of AMPK in reducing inflammatory responses and cellular senescence during the development of emphysema. Therefore, we hypothesize that AMPK reduces inflammatroy responses, senescence, and lung injury. To test this hypothesis, human bronchial epithelial cells (BEAS-2B) and small airway epithelial cells (SAECs) were treated with cigarette smoke extract (CSE) in the presence of a specific AMPK activator (AICAR, 1 mM) and inhibitor (Compound C, 5 mu M). Elastase injection was performed to induce mouse emphysema, and these mice were treated with a specific AMPK activator metformin as well as Compound C. AICAR reduced, whereas Compound C increased CSE-induced increase in IL-8 and IL-6 release and expression of genes involved in cellular senescence. Knockdown of AMPKa1/a2 increased expression of pro-senescent genes (e.g., p16, p21, and p66shc) in BEAS-2B cells. Prophylactic administration of an AMPK activator metformin (50 and 250 mg/kg) reduced while Compound C (4 and 20 mg/kg) aggravated elastase-induced airspace enlargement, inflammatory responses and cellular senescence in mice. This is in agreement with therapeutic effect of metformin (50 mg/kg) on airspace enlargement. Furthermore, metformin prophylactically protected against but Compound C further reduced mitochondrial proteins SOD2 and SIRT3 in emphysematous lungs. In conclusion, AMPK reduces abnormal inflammatory responses and cellular senescence, which implicates as a potential therapeutic target for COPD/emphysema.
引用
收藏
页码:22513 / 22523
页数:11
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