title: Metformin reduces airway inflammation and remodeling via activation of AMP-activated protein kinase.
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.
authors.affiliation: Department of Internal Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea.
authors.forename: Chan Sun
authors.initials: CS
authors.lastname: Park
authors.forename: Bo-Ram
authors.initials: BR
authors.lastname: Bang
authors.forename: Hyouk-Soo
authors.initials: HS
authors.lastname: Kwon
authors.forename: Keun-Ai
authors.initials: KA
authors.lastname: Moon
authors.forename: Tae-Bum
authors.initials: TB
authors.lastname: Kim
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
authors.forename: Hee-Bom
authors.initials: HB
authors.lastname: Moon
authors.forename: You Sook
authors.initials: YS
authors.lastname: Cho
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000517:prevention & control*; D001483:Base Sequence; D015153:Blotting, Western; D017931:DNA Primers; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D017931:DNA Primers; D005353:Fibronectins; D053773:Transforming Growth Factor beta1; D008687:Metformin; D055372:AMP-Activated Protein Kinases