Oncotarget

Research Papers:

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

Xiao-Yu Cheng, Yang-Yang Li, Cheng Huang, Jun Li and Hong-Wei Yao _

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Oncotarget. 2017; 8:22513-22523. https://doi.org/10.18632/oncotarget.15116

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Abstract

Xiao-Yu Cheng1, Yang-Yang Li1, Cheng Huang1, Jun Li1, Hong-Wei Yao1

1School of Pharmacy, Anhui Medical University, Hefei, The People's Republic of China

Correspondence to:

Jun Li, email: lijun@ahmu.edu.cn

Hong-Wei Yao, email: yhgwei@hotmail.com

Keywords: cigarette smoke, AMPK, SIRT3, mitochondrial dysfunction, COPD

Received: August 15, 2016     Accepted: January 23, 2017     Published: February 06, 2017

ABSTRACT

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 μM). 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 AMPKα1/α2 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.


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