Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Int Immunopharmacol. 2022 Jan;102:108405. doi: 10.1016/j.intimp.2021.108405. Epub 2021 Dec 2.
Inflammatory bowel disease (IBD) is an autoimmune disease involving intestinal tissue. IBD activates a series of cell death pathways. Pyroptosis is recently identified as a critical cell death pathway in IBD associated with the activation of caspase-1. VX765 is a caspase-1 inhibitor that can be converted to VRT-043198 in vivo. This study was designed to explore the therapeutic effect of VX765 on colitis using a dextran sulfate sodium (DSS)-induced colitis model in mice. In this research, the caspase-1 inhibitor on inflammatory, pyroptosis, apoptosis, macrophage activation, and intestinal barrier were investigated. We found that administration of VX765 attenuated body weight loss, colonic shortening, and colonic pathological injury in mice. Our study also revealed a therapeutic effect of VX765 on colitis in a dose-dependent manner. VX765 inhibited pyroptosis by curbing the Caspase-1/GSDMD pathway and its downstream key inflammatory cytokines--IL-1β and IL-18. These results indicated that VX765 might have a dose-dependent therapeutic effect on DSS-induced colitis in mice.
炎症性肠病（IBD）是一种涉及肠道组织的自身免疫性疾病。IBD 激活了一系列细胞死亡途径。细胞焦亡最近被确定为与 caspase-1 激活相关的 IBD 关键细胞死亡途径。VX765 是一种 caspase-1 抑制剂，在体内可转化为 VRT-043198。本研究旨在使用葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型探索 VX765 对结肠炎的治疗作用。在这项研究中，研究了 caspase-1 抑制剂对炎症、细胞焦亡、细胞凋亡、巨噬细胞激活和肠屏障的影响。我们发现，VX765 给药可减轻小鼠的体重减轻、结肠缩短和结肠病理损伤。我们的研究还表明，VX765 对结肠炎具有剂量依赖性的治疗作用。VX765 通过抑制 Caspase-1/GSDMD 途径及其下游关键炎症细胞因子-IL-1β 和 IL-18 来抑制细胞焦亡。这些结果表明，VX765 可能对 DSS 诱导的结肠炎具有剂量依赖性的治疗作用。
