Department of Pediatrics, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Drug Dev Res. 2022 Sep;83(6):1455-1466. doi: 10.1002/ddr.21975. Epub 2022 Jul 21.
The aim of this study was to elucidate the mechanism underlying the effects of Kukoamine A (KuA) treatment on endotoxin-induced lung injury/inflammation. The study was performed in lipopolysaccharide (LPS)-exposed mouse models of lung injury and LPS-induced alveolar epithelial cell model. Relevant kits were used to detect levels of inflammation-related indicators, oxidative stress indicators, and mitochondrial function. Hematoxylin and eosin staining was to detect lung injury. Then, C-C motif chemokine receptor 5 (CCR5) overexpression plasmid was transfected into alveolar epithelial cells to investigate the mechanism of KuA in lung injury. The results showed that LPS induction increased the expression of inflammatory factors, oxidative stress markers, and mitochondrial dysfunction in both animal and cellular models. In the mouse model, KuA treatment improved lung tissue injury, decreased wet-to-dry ratio and MPO levels, reduced the expression of inflammatory factors, and ameliorated oxidative stress and mitochondrial dysfunction. The protective effect of KuA in the cell model remained whereas was markedly reversed after CCR5 overexpression. Taken together, KuA might improve LPS-induced lung injury by inhibiting CCR5. This might also provide a novel theory for KuA in the treatment of lung injury.
本研究旨在阐明库卡胺 A (KuA) 治疗对内毒素诱导的肺损伤/炎症的作用机制。该研究在脂多糖 (LPS) 暴露的小鼠肺损伤模型和 LPS 诱导的肺泡上皮细胞模型中进行。使用相关试剂盒检测炎症相关指标、氧化应激指标和线粒体功能水平。苏木精和伊红染色用于检测肺损伤。然后，将 C-C 基序趋化因子受体 5 (CCR5) 过表达质粒转染到肺泡上皮细胞中，以研究 KuA 在肺损伤中的作用机制。结果表明，LPS 诱导增加了动物和细胞模型中炎症因子、氧化应激标志物和线粒体功能障碍的表达。在小鼠模型中，KuA 治疗改善了肺组织损伤，降低了湿重/干重比和 MPO 水平，减少了炎症因子的表达，并改善了氧化应激和线粒体功能障碍。KuA 在细胞模型中的保护作用仍然存在，但在 CCR5 过表达后明显逆转。综上所述，KuA 可能通过抑制 CCR5 改善 LPS 诱导的肺损伤。这也为 KuA 在肺损伤治疗中的应用提供了新的理论依据。
