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Updated: Sep 24, 2025
Phenotyping Mouse Pulmonary Function In Vivo with the Lung Diffusing Capacity
Published on: January 6, 2015
Metformin suppresses epithelial sodium channel hyperactivation and its associated phenotypes in a mouse model of
Ryunosuke Nakashima1, Hirofumi Nohara2, Noriki Takahashi2
1Department of Molecular Medicine, Graduate School of Pharmaceutical Science, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.
Abstract:
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world, and has no radical treatment. Inhibition of amiloride-sensitive epithelial sodium ion channel (ENaC) has now been considered as a potential therapeutic target against COPD. One possible modulator of ENaC is AMP-activated protein kinase (AMPK), a key molecule that controls a wide variety of cellular signals; however, little is known about whether metformin, a clinically available AMPK activator, has a protective role against ENaC-associated chronic pulmonary phenotypes, such as emphysema and pulmonary dysfunction. We first used ENaC-overexpressing human bronchial epithelial cells (β/γENaC-16HBE14o-) and identified that Metformin significantly reduced ENaC activity. Consistently, in vivo treatment of ENaC-overexpressing COPD mouse model (C57BL/6-βENaC-Tg mice) showed improvement of emphysema and pulmonary dysfunction, without any detrimental effect on non-pulmonary parameters (blood glucose level etc.). Bronchoalveolar lavage fluid (BALF) and lung tissue analyses revealed significant suppression in the infiltration of neutrophils as well as the expression of inflammatory markers (KC), neutrophil gelatinase (MMP9) and macrophage elastase (MMP12) in metformin-treated C57BL/6-βENaC-Tg mice. Overall, the present study demonstrates that metformin directly inhibits ENaC activity in vitro and provides the first evidence of therapeutical benefit of Metformin for COPD with higher ENaC activity.
Insights
Metformin, an AMP-activated protein kinase (AMPK) activator, was found to inhibit epithelial sodium channel (ENaC) activity. This study provides evidence that metformin offers therapeutic benefits for chronic obstructive pulmonary disease (COPD) by reducing lung inflammation and dysfunction.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Cell Biology
Background:
- Chronic obstructive pulmonary disease (COPD) is a major global health concern with limited treatment options.
- Inhibition of the epithelial sodium channel (ENaC) is a potential therapeutic strategy for COPD.
- The role of metformin, an AMP-activated protein kinase (AMPK) activator, in COPD associated with ENaC is not well understood.
Purpose of the Study:
- To investigate the effect of metformin on ENaC activity in vitro.
- To evaluate the therapeutic potential of metformin in a mouse model of COPD with ENaC overexpression.
- To determine the impact of metformin on pulmonary inflammation and dysfunction in COPD.
Main Methods:
- Utilized ENaC-overexpressing human bronchial epithelial cells (β/γENaC-16HBE14o-) to assess metformin's effect on ENaC activity.
- Administered metformin to a transgenic mouse model (C57BL/6-βENaC-Tg) overexpressing ENaC to mimic COPD.
- Analyzed bronchoalveolar lavage fluid (BALF) and lung tissues for inflammatory markers and cellular infiltration.
Main Results:
- Metformin significantly inhibited ENaC activity in vitro.
- In vivo treatment improved emphysema and pulmonary function in the COPD mouse model without adverse effects on other parameters.
- Metformin treatment suppressed neutrophil infiltration and reduced the expression of inflammatory markers (KC, MMP9, MMP12) in the lungs.
Conclusions:
- Metformin directly inhibits ENaC activity.
- Metformin demonstrates therapeutic benefits in a preclinical COPD model characterized by ENaC overexpression.
- This study presents the first evidence for metformin's efficacy in treating COPD with elevated ENaC activity.
