Zhang Lin, Cheng Jian, Shen Jie, Wang Sheng, Guo Chuanyong, Fan Xiaoming
Department of Gastroenterology, Jinshan Hospital, Fudan University, Shanghai, China.
Center of Emergency and Intensive Care Unit, Jinshan Hospital, Fudan University, Shanghai, China.
Front Pharmacol. 2021 Mar 10;12:661853. doi: 10.3389/fphar.2021.661853. eCollection 2021.
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) that occurs in the lining of the rectum and colon. Apoptosis of the intestinal epithelial cells (IECs) is common in active UC patients. Ghrelin is reported to be downregulated in apoptosis of IECs induced by tumor necrosis factor-α (TNF-α). Therefore, we hypothesized that ghrelin might play an antiapoptotic role in UC progression, which was investigated using and studies. The TNF-α-treated Caco-2 cell model and mouse colitis model induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS) were established and employed. We found that ghrelin could inhibit the apoptosis of Caco-2 cells induced by TNF-α, which could be disturbed by [D-lys3]-GHRP-6, the antagonist of ghrelin receptor GHS-R1a. Similarly, in the DSS- and TNBS-induced mouse colitis models, ghrelin could also protect intestinal tissues from apoptosis in DSS- and TNBS-induced colitis depending on GHS-R1a. Furthermore, ghrelin modulated the unfolded protein response (UPR) pathway and regulated the expressions of caspase-3, BAX, and Bcl-2, which contributed to the inhibition of cell apoptosis. In conclusion, ghrelin protects IECs from apoptosis during the pathogenesis of colitis by regulating the UPR pathway.
溃疡性结肠炎（UC）是一种炎症性肠病（IBD），发生于直肠和结肠的黏膜层。在活动期UC患者中，肠上皮细胞（IECs）凋亡很常见。据报道，胃饥饿素在肿瘤坏死因子-α（TNF-α）诱导的IECs凋亡中表达下调。因此，我们推测胃饥饿素可能在UC进展中发挥抗凋亡作用，并使用[具体研究方法1]和[具体研究方法2]进行了研究。建立并应用了TNF-α处理的Caco-2细胞模型以及由葡聚糖硫酸钠（DSS）或2,4,6-三硝基苯磺酸（TNBS）诱导的小鼠结肠炎模型。我们发现胃饥饿素可以抑制TNF-α诱导的Caco-2细胞凋亡，而胃饥饿素受体GHS-R1a的拮抗剂[D-lys3]-GHRP-6可干扰这一过程。同样，在DSS和TNBS诱导的小鼠结肠炎模型中，胃饥饿素也可依赖GHS-R1a保护肠道组织免受DSS和TNBS诱导的结肠炎中的细胞凋亡。此外，胃饥饿素调节未折叠蛋白反应（UPR）途径并调节半胱天冬酶-3、BAX和Bcl-2的表达，这有助于抑制细胞凋亡。总之，胃饥饿素通过调节UPR途径在结肠炎发病过程中保护IECs免受凋亡。
