Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; The Third Affiliated Hospital of Soochow University, Changzhou 213000, China.
Laboratory Animal Center, Wenzhou Medical University, Wenzhou 325000, China.
Eur J Pharmacol. 2019 Jun 5;852:151-158. doi: 10.1016/j.ejphar.2019.02.042. Epub 2019 Feb 23.
Inflammation plays an important role in acute lung injury (ALI). Hesperetin (HES), a natural flavanone and an aglycone of hesperidin, has established potent anti-inflammatory activity. The aim of this study was to evaluate the potential protective effect of HES on lipopolysaccharide (LPS)-induced ALI in mice and to illuminate its possible directly target. Results indicated that HES pretreatment significantly attenuated LPS-induced pulmonary pathological injury, total protein concentration, markedly decreased the number of neutrophils and the levels of inflammatory cytokines, TNF-α and IL-6, in ALI model in vivo and in vitro. Meanwhile, pretreatment with HES dramatically reduced myeloperoxidase (MPO) activity in LPS-induced ALI mice. Additionally, using molecular docking and co-immunoprecipitation assay, HES showed a directly bind with myeloid differentiation 2 (MD2), in which HES could inhibit MAPK activation, regulate IκB degradation, block the interaction MD2 and its co-receptor Toll-like receptor 4 (TLR4). Taken together, HES showed a significantly protective effect against LPS-induced ALI, which might be associated with MD2 protein. These results attested HES worthy of further progress into an adjunctive potential drug for the treatment for ALI.
炎症在急性肺损伤 (ALI) 中起着重要作用。橙皮素 (HES) 是一种天然类黄酮，也是橙皮苷的苷元，具有很强的抗炎活性。本研究旨在评价 HES 对脂多糖 (LPS) 诱导的小鼠 ALI 的潜在保护作用，并阐明其可能的直接靶标。结果表明，HES 预处理可显著减轻 LPS 诱导的肺组织病理损伤，降低总蛋白浓度，显著减少中性粒细胞数量和炎症细胞因子 TNF-α和 IL-6 的水平，在体内和体外的 ALI 模型中均有明显效果。同时，HES 预处理可显著降低 LPS 诱导的 ALI 小鼠髓过氧化物酶 (MPO) 活性。此外，通过分子对接和共免疫沉淀实验，HES 与髓样分化因子 2 (MD2) 有直接结合，HES 可抑制 MAPK 激活，调节 IκB 降解，阻断 MD2 与其共受体 Toll 样受体 4 (TLR4) 的相互作用。综上所述，HES 对 LPS 诱导的 ALI 具有显著的保护作用，可能与 MD2 蛋白有关。这些结果表明 HES 有潜力成为治疗 ALI 的辅助药物。
