Metformin mitigates sepsis-associated pulmonary fibrosis by promoting ampk activation and inhibiting hif-1-induced aerobic glycolysis

Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis (PF). However, at present, the mechanism and pathogenesis remain unclear. We aimed to test the hypothesis that the adenosine monophosphate-activated protein kinase (AMPK) activation and suppression of hypoxia-inducible factor 1 alpha (HIF-1 alpha)-induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide increased fibroblast activation through AMPK inactivation, HIF-1 alpha induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1 alpha inhibition. In addition, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1 alpha expression and alleviates PF associated with sepsis, which is caused by aerobic glycolysis, in mice. Hypoxia-inducible factor 1 alpha knockdown demonstrated similar protective effects in vivo. Our research implies that targeting AMPK activation and HIF-1 alpha-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated PF.