Metabolic Reprograming in Alveolar Epithelial Cells Type 2: Repurposing Old Drugs for Emphysema Treatment

Joselyn Rojas-Quintero, MSc, MD
Credit: American Lung Association

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease. Environmental and genetic factors highly affect the lung, which is composed of at least 40 types of cells, including the stem-like alveolar epithelial type 2 (AT2) cells.¹ Thus, the cell-to-cell interactions and pathologies in COPD are still largely understood.

Metabolically speaking, AT2 cells run “a tight ship”. AT2 cells are in charge of pulmonary surfactant synthesis, lamellar bodies assembly, and secretion into the alveolar lumen.² Pulmonary surfactant is a complex lipoprotein, essential for lung function and whose absence is considered incompatible for life.^2,3 Fatty acids are the main fuel for AT2 cells, thus fatty acid synthesis and turnover are critical, especially relating to palmitate and steric acids. Enzymes like fatty acid synthase (FASN) lead the synthesis process.⁴

Cigarette smoke is a major risk factor for emphysema development, partially by inducing AT2 cell loss. Besides the direct oxidative stress damage caused by the smoke itself, AT2 cells suffer metabolic reprogramming. In vitro and murine studies have shown that cigarette smoke blunts glycolysis pathway, leading to use of palmitate for β-oxidation and ATP generation.⁵

In particular, palmitate acid gets shuttled away from surfactant production while dipalmitoylphosphatidylcholine (DPPC) production is significantly reduced. The accelerated and persistent β-oxidation causes oxidative stress due to mitochondrial generation of free radicals, and ultimately, AT2 cell loss. Given the importance of AT2 cells in repairing the injured alveoli and maintaining alveoli number and lumen size, COPD ideal therapies should either improve AT2 cells biology and/or increase AT2 cells numbers.

Metformin, a biguanide known for inhibiting mitochondrial-complex-I,⁶ is a pleiotropic drug capable of restoring glucose metabolism and insulin sensitivity, improving mitochondrial health by AMPK activation, reduction of oxidative stress, and exerting anti-aging and anti-cancer effects. Considering this plethora of biological effects, we first tested the theory that metformin protects mice from cigarette smoke-induced emphysema. Mice exposed to cigarette smoke and given metformin during the second half of exposures exhibited significant reduction of emphysema, airway remodeling, epithelial cell apoptosis, lipoperoxidation, and DNA damage. Moreover, metformin significantly improved lung telomere length, suggesting that it’s able to reverse accelerated aging in these mice. Concordantly, we also reported that COPD patients who are persistent metformin users from the COPD gene cohort have reduced emphysema progression.⁷

We further characterized the role of metformin in AT2 cells metabolism. We determined that in human AT2 cells, metformin is capable of significantly reducing apoptosis and oxidative stress in smokers and COPD patients. In murine AT2 alveolospheres, metformin intervention rescues AT2 cell loss, reduces active caspase-3 production, restores the expression of FASN which impacts surfactant production, ATP production is improved via carnitin-palmytoyltransferase-1A expression. Moreover, bulk RNASeq data from AT2 alveolospheres shows that metformin-treated organoids have reduced DNA damage, improved tricyclic cycle and overall mitochondrial bioenergetics.

Cross-sectional studies have shown that COPD patients who are metformin users for diabetes control have significantly lower all-cause ER visits and hospitalizations.^8,9 Even though there is a potential risk for lactate acidosis (1:100,000 patients),¹⁰ COPD subjects who are metformin users have increased survival benefit from the drug’s use.¹¹ Finally, metformin reduces the risk of lung cancer in diabetic users, and improves survival in those living with lung cancer.^12,13

COPD patients are indeed complex patients. First, COPD is an independent risk factor for lung cancer. Second, COPD patients exhibit an array of systemic metabolic diseases including metabolic syndrome, muscle wasting, cardiovascular disease, osteopenia, obstructive and sleep apnea. Given that metformin has beneficial effects in every one of these comorbidities and at the same time it slows down emphysema progression, it is time to assess the tangible opportunity of repurposing a known and safe drug towards COPD management. Therefore, further mechanistic studies deciphering the role of metformin in lung physiology, especially in the enigmatic AT2 cells, is essential to pave the way for appropriate clinical trials.

References

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