Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment
Open accessAbstract
Rationale: Cigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, and emphysema, as well as systemic pathologies. Metformin is beneficial for protecting against aging-related diseases. Objectives: We sought to investigate whether metformin may ameliorate CS-induced pathologies of emphysematous chronic obstructive pulmonary disease (COPD). Methods: Mice were exposed chronically to CS and fed metformin-enriched chow for the second half of exposure. Lung, kidney, and muscle pathologies, lung proteostasis, endoplasmic reticulum (ER) stress, mitochondrial function, and mediators of metformin effects in vivo and/or in vitrowere studied. We evaluated the association of metformin use with indices of emphysema progression over 5 years of follow-up among the COPDGene (Genetic Epidemiology of COPD) study participants. The association of metformin use with the percentage of emphysema and adjusted lung density was estimated by using a linear mixed model. Measurements and Main Results: Metformin protected against CS-induced pulmonary inflammation and airspace enlargement; small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro; and ER stress. The AMPK (AMP-activated protein kinase) pathway was central to metformin’s protective action. Within COPDGene, participants receiving metformin compared with those not receiving it had a slower progression of emphysema (−0.92%; 95% confidence interval [CI], −1.7% to −0.14%; P = 0.02) and a slower adjusted lung density decrease (2.2 g/L; 95% CI, 0.43 to 4.0 g/L; P = 0.01). Conclusions: Metformin protected against CS-induced lung, renal, and muscle injury; mitochondrial dysfunction; and unfolded protein responses and ER stress in mice. In humans, metformin use was associated with lesser emphysema progression over time. Our results provide a rationale for clinical trials testing the efficacy of metformin in limiting emphysema progression and its systemic consequences.
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Metformin has been shown to protect against CS-induced myofiber type switch and telomere shortening in a mouse model of emphysema, mediated by activation of AMPK and GDF-15.
“On a therapeutic prospect, the metabolic modulator metformin has been shown to be able to protect against CS-induced myofibers’ type switch and telomere shortening in a mouse model of emphysema, mediated by the activation of 5′AMPK (AMP-activated protein kinase) and GDF-15 (growth differentiation factor 15) [146].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [146]
The Results report that metformin-treated, cigarette-smoke-exposed mice had longer quadriceps telomeres and were partially protected against loss of type I muscle fibers. The Abstract and Discussion link metformin’s protective effects to AMPK and GDF-15 activation, but do not establish that activation of both mediates these specific muscle and telomere effects. (LLM, conf=0.85)
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The future drug treatment of COPD
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Post-COPD: Can Emphysema Be Repaired?
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Principaux messages de la première Biennale BPCO 2021 de la SPLF. Mieux comprendre pour innover
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- Authors
- Polverino, F., Wu, T. D., Rojas-Quintero, J., Wang, X., Mayo, J., Tomchaney, M., Tram, J., Packard, S., Zhang, D., Cleveland, K. H., Cordoba-Lanus, E., Owen, C. A., Fawzy, A., Kinney, G. L., Hersh, C. P., Hansel, N. N., Doubleday, K., Sauler, M., Tesfaigzi, Y., Ledford, J. G., Casanova, C., Zmijewski, J., Konhilas, J., Langlais, P. R., Schnellmann, R., Rahman, I., McCormack, M., & Celli, B.
- Affiliations
- Asthma and Airway Disease Research Center and
- Michael E. DeBakey VA Medical Center (US)
- Division of Pulmonary and Critical Care Medicine and
- University of Georgia (US)
- College of Pharmacy, and
- Servicio de Neumología, Unidad de Investigación, Hospital Universitario La Candelaria, Santa Cruz de Tenerife, Tenerife, Spain
- Johns Hopkins University (US)
- Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado
- Brigham and Women's Hospital (US)
- Division of Endocrinology, Department of Medicine
- Yale University (US)
- Hospital Universitario Nuestra Señora de Candelaria (ES)
- University of Alabama at Birmingham (US)
- University of Arizona (US)
- University of Rochester Medicine (US)
- Corresponding author
- Polverino, Francesca
- ORCID
- Polverino, Francesca
- Wu, Tianshi David
- Wang, Xiaoyun
- Tomchaney, Michael
- Packard, Samuel
- Zhang, Duo
- Owen, Caroline A.
- Fawzy, Ashraf
- Hersh, Craig P.
- Hansel, Nadia N.
- Doubleday, Kevin
- Sauler, Maor
- Tesfaigzi, Yohannes
- Ledford, Julie G.
- Casanova, Ciro
- Zmijewski, Jaroslaw
- Konhilas, John
- Langlais, Paul R.
- Schnellmann, Rick
- Rahman, Irfan
- McCormack, Meredith
- Venue
- American Journal of Respiratory and Critical Care Medicine
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-09
- Volume
- 204
- Issue
- 6
- Pages
- 651-666
- ISSN
- 1073-449X (ISSN-L)
- 1535-4970
- PMC
- PMC8521702
- OpenAlex
- W3164074497
- Cited by
- 100
- References
- 52
- Citations by year
- 2026: 15 · 2025: 17 · 2024: 19 · 2023: 28 · 2022: 16 · 2021: 5
- FWCI
- 11.04
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory and Critical Care Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (UL1TR001863)
- National Heart, Lung, and Blood Institute (K08HL135402, U01HL089856, U01HL089897, R01HL149744, R01HL155948, R01HL142769, R01HL132523, R01HL139617)
- National Institute of Environmental Health Sciences (P50ES018176, T32ES007091)
- National Center for Advancing Translational Sciences
- National Institute on Minority Health and Health Disparities (P50MD010431)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Keywords
- metformin, emphysema, chronic obstructive pulmonary disease, cigarette smoke, AMPK signaling, endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, aging, COPDGene, lung aging, kidney injury, muscle damage, small airway remodeling, emphysema progression
- MeSH terms
- Cigarette Smoking, Aged, Aged, 80 and over, Animals, Female, Follow-Up Studies, Humans, Male, Metformin, Mice, Inbred C57BL, Middle Aged, Pulmonary Emphysema, Biomarkers, Treatment Outcome, Disease Progression, Protective Agents, Pulmonary Disease, Chronic Obstructive, Mice
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