Metformin reduced CS-induced senescence-associated β-galactosidase in experimental model of chronic obstructive pulmonary disease
Tatt Jhong Haw (1, 2), Lohis Balachandran (1, 2), Michael Fricker (1, 2), Jay Horvat (1, 2) and Philip Hansbro (3)
Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia
School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia
The Centre for Inflammation, Centenary Institute, and Faculty of Science, University of Technology Sydney, New South Wales, Australia
Lung function declines naturally with increasing age, however, this is substantially increased in chronic obstructive pulmonary disease (COPD). COPD is the 3rd leading cause of death worldwide with cigarette smoke (CS) as a major cause. It is a heterogeneous debilitating lung disease characterized by persistent lung inflammation, airway fibrosis and emphysema (alveolar enlargement). These lead to rapid decline in lung function and severe breathing difficulties. Recent studies in humans and mice indicate that premature aging (senescence) may play roles in COPD. However, the underlying mechanisms remain poorly understood. Metformin, a glucose-lowering anti-diabetic drug, was shown to reduce senescence in vitro and reduce the risk of COPD in diabetic patients. We hypothesized that metformin would reduce CS-induced disease severity and senescence in a mouse model of experimental COPD and will be valuable in delineating the underlying mechanisms.
BALB/c mice (6-7 weeks old) were subjected to nose-only inhalation of CS or normal air (controls) for up to 12 weeks to induce the hallmark features of COPD. Some mice were treated with metformin (200mg/kg, in drinking water). The impact of metformin on disease features (airway inflammation, airway fibrosis, alveolar enlargement & lung function) and senescence-associated β-galactosidase (SABG) were assessed.
Metformin reduced CS-induced airway inflammation, influx of leukocytes (predominantly macrophages & neutrophils) in bronchoalveolar lavage. CS-induced oxidative stress-associated genes such as NADPH quinone dehydrogenase 1 and glutamate-cysteine ligase catalytic subunit were reduced in mice treated with metformin. Metformin also reduced CS-induced airway fibrosis (collagen deposition), but not alveolar enlargement, and improved lung function. Importantly, immunohistochemistry showed that metformin reduced CS-induced SABG on small airway epithelial cells, vascular endothelial cells and lung parenchyma.
Our findings show that metformin concomitantly reduced severity of CS-induced experimental COPD and SABG. Further studies will delineate the mechanisms and identify novel senescence-specific therapeutic targets for COPD.