Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase
Graphical abstract
Introduction
Asthma has unique characteristics, such as reversible airway obstruction and airway hyperresponsiveness (AHR) that are typically associated with chronic inflammation. Although airway obstruction is fully reversible with treatment in many cases, persistent airflow limitation and progressive decline of lung function are also observed in some patients. Structural changes, widely referred to airway remodeling, are critical for the development of irreversible airway obstruction and are linked to the morbidities of severe asthma. Although chronic airway inflammation is a key contributing factor for airway remodeling, the presence of airway inflammation does not always translate into airway remodeling. Despite appropriate inhaled corticosteroid treatments, the most effective current anti-inflammatory therapy [1], [2], many studies have demonstrated that corticosteroids have little or no effect on airway remodeling [3], [4]. Thus, elucidation of the precise mechanisms and development of novel therapeutic approaches targeting airway remodeling and chronic inflammation in asthma are urgently needed.
Recent reports have shown that metformin, a medication commonly used for treating type 2 diabetes, has various biological functions other than its anti-diabetic effects. Metformin suppressed tumor necrosis factor-α (TNFα) production in a variety of cells, including human monocytes, umbilical vein endothelial cells, and primary bronchial epithelial cells [5], [6], [7]. Two in vivo studies demonstrated that metformin administration reduced experimental autoimmune encephalomyelitis (EAE) induction and improved survival rates during endotoxemia [8], [9]. The cellular mechanism of metformin may involve adenosine mono-phosphate activated protein kinase (AMPK), a sensor of cellular energy status and oxidative stress. AMPK may function in cellular proliferation and protein synthesis, and it suppresses NADPH oxidases that generate oxidative stress [10]. Furthermore, roles of AMPK in tissue remodeling, especially during vascular remodeling and cardiac hypertrophy, have been reported [11], [12].
Based on previous studies, metformin may have both anti-inflammatory and anti-airway remodeling effects during chronic asthma through AMPK activation. Currently, few studies have been conducted to elucidate the roles of metformin in the pathogenesis of airway inflammation and remodeling in asthma. We evaluated the effect of metformin on airway inflammation and remodeling and its functional mechanism in a murine model of chronic asthma.
Section snippets
Mice
Female, 6–8-weeks-old BALB/C mice were purchased from OrientBio (Kapyong, Korea). Heterozygous AMPKα1-deficient (AMPKα1 HT) C57BL/6 mice were generously provided by Professor Benoit Violet (INSERM U567, Paris, France) and bred in specific pathogen-free conditions. Animal experiments were approved by the Institutional Animal Care and Use Committee of Asan Medical Center, Seoul, Korea.
Generation of a murine asthma model
To generate a chronic asthma model, mice were immunized with ovalbumin (OVA) and fungal-associated allergenic
Metformin attenuates eosinophilic airway inflammation and remodeling in OVA-and FAP-induced chronic asthma models
We examined whether metformin could reduce allergic airway inflammation in murine models of chronic asthma. Mice challenged with repetitive OVA or FAP had enhanced lung tissue inflammation and elevated levels of inflammatory cells. With metformin treatment, the number of inflammatory cells in BALF, especially eosinophils, was decreased in metformin-treated mice than that in sham-treated mice (Fig. 2A and B). Consistent with bronchial inflammatory cells, histopathological examination
Discussion
We have demonstrated that metformin significantly reduces airway inflammation and airway remodeling in a murine model of chronic asthma at least partially through AMPK activation. Thus, metformin may function as a novel anti-asthmatic agent and AMPK may be a target molecule for the development of new drugs targeting both airway inflammation and remodeling in bronchial asthma.
Metformin possesses various properties other than its anti-diabetic effects. Several in vitro and in vivo studies
Author contributions
Conception and design, Chan Sun Park, Ki-Young Lee, Hee-Bom Moon, and You Sook Cho.; analysis and interpretation, Chan Sun Park, Bo-Ram Bang, Hyouk-Soo Kwon, and Keun-Ai Moon.; drafting the manuscript for important intellectual content, Chan Sun Park, Bo-Ram Bang, and You Sook Cho.; revising the manuscript for important intellectual content, Chan Sun Park, Hyouk-Soo Kwon, Tae-Bum Kim, Ki-Young Lee and You Sook Cho.; and final approval of the manuscript, Chan Sun Park, Bo-Ram Bang, Hyouk-Soo
Conflict of interest
There is no other relationships/conditions/circumstances that present a potential conflict of interest.
Acknowledgments
This work was supported by a grant (no. 2012-302) from Asan Life and Science Institute to Y.S.C. & a grant (no. 20090086092) from National Research Foundation (NRF) to Y.S.C.
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These authors equally contributed to this article.