Abstract
Recent research has revealed that aerobic glycolysis has a strong correlation with sepsis-associated pulmonary fibrosis. 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 1α (HIF-1α) induced aerobic glycolysis play a central role in septic pulmonary fibrogenesis. Cellular experiments demonstrated that lipopolysaccharide (LPS) increased fibroblast activation through AMPK inactivation, HIF-1α induction, alongside an augmentation of aerobic glycolysis. By contrast, the effects were reversed by AMPK activation or HIF-1α inhibition. Additionally, pretreatment with metformin, which is an AMPK activator, suppresses HIF-1α expression and alleviates pulmonary fibrosis associated with sepsis, which is caused by aerobic glycolysis, in mice. HIF-1α knockdown demonstrated similar protective effects in vivo. Our research implies that targeting AMPK activation and HIF-1α-induced aerobic glycolysis with metformin might be a practical and useful therapeutic alternative for sepsis-associated pulmonary fibrosis.
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