METFORMIN MITIGATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY PROMOTING AMPK ACTIVATION AND INHIBITING HIF-1α–INDUCED AEROBIC GLYCOLYSIS

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.

Sinomenine ameliorates bleomycin-induced pulmonary fibrosis by inhibiting the differentiation of fibroblast into myofibroblast

“…To investigate the effects of SIN on TGF-β1-induced metabolic reprogramming, we employed the Seahorse Bioscience Extracellular Flux Analyzer to monitor the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) of fibroblasts following TGF-β1 and SIN treatment. Consistent with previous studies [ 11 , 19 ], TGF-β1 treatment significantly enhanced glycolysis and glycolytic activity ( Fig. 6 A–C), while attenuating basal respiration and maximal respiration ( Fig.…”

LPS-induced monocarboxylate transporter-1 inhibition facilitates lactate accumulation triggering epithelial-mesenchymal transformation and pulmonary fibrosis

“…A total of 48 healthy mice were randomly divided into sham (n = 6), LPS (n = 18), MCT1OE (n = 6), MCT1OE + LPS (n = 18) groups. In LPS group and MCT1OE + LPS group, animals were injected intraperitoneally with LPS (5 mg/kg, Escherichia coli O127:B8, Sigma, USA) for 3 consecutive days while mice were injected with saline instead in sham group and MCT1OE group, which was optimized on the basis of other investigator and our previous research [ 13 , 16 , 17 ].…”

Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review

“…It is hypothesized that adding a phosphate group would cause a conformational change in the ACE2 receptor, leading to decreased virus binding [123]. AMPK activation has also been involved in pulmonary fibrosis during severe infections, and metformin has been shown to prevent pulmonary fibrosis [124,125]. COVID-19 infection has also been shown to increase pulmonary fibrosis.…”