American journal of respiratory and critical care medicine | 2021
Metformin: Experimental and Clinical Evidence for a Potential Role in Emphysema Treatment.
Abstract
INTRODUCTION\nCigarette smoke (CS) inhalation triggers oxidative stress and inflammation, leading to accelerated lung aging, apoptosis, emphysema, and systemic pathologies. Metformin is beneficial against aging-related diseases, and we hypothesized that it may ameliorate CS-induced pathologies of emphysematous COPD.\n\n\nMETHODS\nMice were exposed chronically to CS and fed metformin 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 vitro were studied. We evaluated the association of metformin use with indices of emphysema progression over five years of follow-up among the COPDGene Study participants. The association of metformin use with percent emphysema and adjusted lung density was estimated with a linear mixed model.\n\n\nRESULTS\nMetformin protected against CS-induced pulmonary inflammation, airspace enlargement, and small airway remodeling, glomerular shrinkage, oxidative stress, apoptosis, telomere damage, aging, dysmetabolism in vivo and in vitro, and ER stress. The AMPK pathway was central to metformin protective action. Within COPDGene, participants taking metformin compared to those not on it had slower progression of emphysema (-0.92%, CI; -1.7 to -0.14%, p = 0.02) and adjusted lung density decrease (2.2 g/L; 95% CI 0.43 to 4.0 g/L, p = 0.01).\n\n\nCONCLUSIONS\nMetformin protected against CS-induced lung, renal, and muscle injury, mitochondrial dysfunction, and UPR-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.