Lee Dahyeon, Park Jeong Seop, Kim Doyoung, Hong Hyun Sook
Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Korea.
East-West Medical Research Institute, Kyung Hee University, Seoul 02447, Korea.
Antioxidants (Basel). 2022 May 7;11(5):920. doi: 10.3390/antiox11050920.
Liver failure is an outcome of chronic liver disease caused by steatohepatitis and cholestatic injury. This study examined substance P (SP) effect on liver injury due to cholestatic stress caused by excessive bile acid (BA) accumulation. Chenodeoxycholic acid (CDCA) was added to HepG2 cells to induce hepatic injury, and cellular alterations were observed within 8 h. After confirming BA-mediated cellular injury, SP was added, and its restorative effect was evaluated through cell viability, reactive oxygen species (ROS)/inflammatory cytokines/endothelial cell media expression, and adjacent liver sinusoidal endothelial cell (LSEC) function. CDCA treatment provoked ROS production, followed by IL-8 and ICAM-1 expression in hepatocytes within 8 h, which accelerated 24 h post-treatment. Caspase-3 signaling was activated, reducing cell viability and promoting alanine aminotransferase release. Interestingly, hepatocyte alteration by CDCA stress could affect LSEC activity by decreasing cell viability and disturbing tube-forming ability. In contrast, SP treatment reduced ROS production and blocked IL-8/ICAM-1 in CDCA-injured hepatocytes. SP treatment ameliorated the effect of CDCA on LSECs, preserving cell viability and function. Collectively, SP could protect hepatocytes and LSECs from BA-induced cellular stress, possibly by modulating oxidative stress and inflammation. These results suggest that SP can be used to treat BA-induced liver injury.
肝衰竭是由脂肪性肝炎和胆汁淤积性损伤引起的慢性肝病的一种结局。本研究检测了P物质（SP）对胆汁酸（BA）过度蓄积所致胆汁淤积应激引起的肝损伤的影响。将鹅去氧胆酸（CDCA）添加到HepG2细胞中以诱导肝损伤，并在8小时内观察细胞变化。在确认BA介导的细胞损伤后，添加SP，并通过细胞活力、活性氧（ROS）/炎性细胞因子/内皮细胞介质表达以及相邻肝窦内皮细胞（LSEC）功能评估其修复作用。CDCA处理在8小时内引发ROS产生，随后肝细胞中IL-8和ICAM-1表达，在处理后24小时加速。半胱天冬酶-3信号被激活，降低细胞活力并促进丙氨酸转氨酶释放。有趣的是，CDCA应激引起的肝细胞改变可通过降低细胞活力和干扰管形成能力来影响LSEC活性。相比之下，SP处理可减少CDCA损伤的肝细胞中的ROS产生并阻断IL-8/ICAM-1。SP处理改善了CDCA对LSECs的影响，保留了细胞活力和功能。总体而言，SP可能通过调节氧化应激和炎症来保护肝细胞和LSECs免受BA诱导的细胞应激。这些结果表明SP可用于治疗BA诱导的肝损伤。
