HMGB1 promotes HLF-1 proliferation and ECM production through activating HIF1-α-regulated aerobic glycolysis

Aerobic glycolysis is a crucial event in fibroblast differentiation, and extracellular matrix (ECM) production in the progression of pulmonary fibrosis (PF). Abnormal high mobility group protein B1 (HMGB1) activation is involved in the pathogenesis of PF. However, whether aerobic glycolysis contributes to HMGB1-induced fibroblast proliferation and ECM production in PF has not yet been determined. In this study, we investigated the effects of HMGB1 on human embryonic lung fibroblast (HLF-1) proliferation, ECM production, and aerobic glycolysis. The lactate dehydrogenase inhibitor oxamic acid (OA), and PFKFB3 inhibitor 3PO were used to block certain crucial steps of aerobic glycolysis. As a result, we observed an increase of HMGB1 in bronchoalveolar lavage fluid (BALF) in bleomycin (BLM)-treated rats as compared to non-treated rats (control group). A concentration-dependent increase of HLF-1 proliferation and expression of α-SMA and α-collagen I were observed in the HMGB1 group, as well as increases of LDHA activation, glucose uptake levels, glycolytic rate, lactate level, and ATP production. OA and 3PO, or suppression of HIF1-α, blocked the effects of HMGB1. In summary, HMGB1 promotes fibroblast proliferation and ECM production though upregulating expression of HIF1-α to induce an increase of aerobic glycolysis.