Elsevier

Biochemical Pharmacology

Volume 84, Issue 12, 15 December 2012, Pages 1660-1670
Biochemical Pharmacology

Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase

https://doi.org/10.1016/j.bcp.2012.09.025Get rights and content

Abstract

Recent reports have suggested that metformin has anti-inflammatory and anti-tissue remodeling properties. We investigated the potential effect of metformin on airway inflammation and remodeling in asthma. The effect of metformin treatment on airway inflammation and pivotal characteristics of airway remodeling were examined in a murine model of chronic asthma generated by repetitive challenges with ovalbumin and fungal-associated allergenic protease. To investigate the underlying mechanism of metformin, oxidative stress levels and AMP-activated protein kinase (AMPK) activation were assessed. To further elucidate the role of AMPK, we examined the effect of 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) as a specific activator of AMPK and employed AMPKα1-deficient mice as an asthma model. The role of metformin and AMPK in tissue fibrosis was evaluated using a bleomycin-induced acute lung injury model and in vitro experiments with cultured fibroblasts. Metformin suppressed eosinophilic inflammation and significantly reduced peribronchial fibrosis, smooth muscle layer thickness, and mucin secretion. Enhanced AMPK activation and decreased oxidative stress in lungs was found in metformin-treated asthmatic mice. Similar results were observed in the AICAR-treated group. In addition, the enhanced airway inflammation and fibrosis in heterozygous AMPKα1-deficient mice were induced by both allergen and bleomycin challenges. Fibronectin and collagen expression was diminished by metformin through AMPKα1 activation in cultured fibroblasts. Therefore metformin reduced both airway inflammation and remodeling at least partially through the induction of AMPK activation and decreased oxidative stress. These data provide insight into the beneficial role of metformin as a novel therapeutic drug for chronic asthma.

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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