Zhu Li, Bin Zhang, Kun Li, Jinghui Yan, Na Li, Lijuan Sun, Wei Zhao
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and metabolic dysregulation in immune cells, particularly macrophages. This study aimed to determine whether resveratrol (RES) delays COPD progression by modulating macrophage inflammatory activation and glycolytic reprogramming through the Toll-like receptor 4/hexokinase 2 (TLR4/HK2) signaling pathway. A COPD mouse model was established by lipopolysaccharide (LPS) instillation combined with cigarette smoke exposure, followed by treatment with RES at 50 mg/kg. Lung histopathology, mean linear intercept (MLI), destructive index (DI), bronchoalveolar lavage fluid (BALF) inflammatory cell counts, cytokine levels, macrophage polarization, and TLR4/HK2 pathway protein expression were assessed. In vitro, LPS-stimulated RAW264.7 macrophages were treated with RES, with or without TLR4 overexpression and HK2 silencing, to evaluate inflammatory responses, M1 polarization, glycolytic activity, and mitochondrial respiration. RES significantly alleviated lung tissue injury, decreased inflammatory scores, MLI, and DI, and reduced BALF inflammatory cell counts in COPD mice. RES also decreased inflammatory cytokine levels, suppressed macrophage M1 polarization, and downregulated TLR4, p-p65, and HK2 expression. In LPS-stimulated macrophages, RES reduced NO, IL-6, TNF-α, glucose uptake, lactate production, and ECAR, while improving OCR. TLR4 overexpression reversed the inhibitory effects of RES on inflammatory activation, M1 polarization, glycolytic reprogramming, and HK2 expression, whereas HK2 silencing partially restored the protective effects of RES under TLR4 overexpression. RES alleviates macrophage inflammatory activation, M1 polarization, and glycolytic reprogramming, in part through inhibition of the TLR4/HK2 pathway, suggesting its therapeutic potential for delaying COPD progression.