de Vallière Cheryl, Bäbler Katharina, Busenhart Philipp, Schwarzfischer Marlene, Maeyashiki Chiaki, Schuler Cordelia, Atrott Kirstin, Lang Silvia, Spalinger Marianne R, Scharl Michael, Ruiz-Castro Pedro A, Hausmann Martin, Rogler Gerhard
Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland.
Zurich Center for Integrative Human Physiology, Zurich, Switzerland.
Inflamm Intest Dis. 2021 Jul 19;6(3):140-153. doi: 10.1159/000517474. eCollection 2021 Sep.
Local extracellular acidification is associated with several conditions, such as ischemia, cancer, metabolic disease, respiratory diseases, and inflammatory bowel disease (IBD). Several recent studies reported a link between IBD and a family of pH-sensing G protein-coupled receptors. Our previous studies point to an essential role for OGR1 (GPR68) in the modulation of intestinal inflammation and fibrosis. In the current study, we evaluated the effects of a novel OGR1 inhibitor in murine models of colitis.
The effects of a novel small-molecule OGR1 inhibitor were assessed in the acute and chronic dextran sulfate sodium (DSS) murine models of colitis. Macroscopic disease indicators of intestinal inflammation were evaluated, and epithelial damage and immune cell infiltration and proliferation were assessed by immunohistochemistry.
The OGR1 inhibitor ameliorated clinical parameters in acute and chronic DSS-induced colitis. In mice treated with the OGR1 inhibitor, endoscopy showed no thickening and normal vascularity, while fibrin was not detected. Histopathological findings revealed a decrease in severity of colonic inflammation in the OGR1 inhibitor group when compared to vehicle-DSS controls. In OGR1 inhibitor-treated mice, staining for the macrophage marker F4/80 and cellular proliferation marker Ki-67 revealed a reduction of infiltrating macrophages and slightly enhanced cell proliferation, respectively. This was accompanied by a reduction in pro-inflammatory cytokines, TNF and IL-6, and the fibrosis marker TGF-β1.
This is the first report providing evidence that a pharmacological inhibition of OGR1 has a therapeutic effect in murine colitis models. Our data suggest that targeting proton-sensing OGR1 using specific small-molecule inhibitors may be a novel therapeutic approach for the treatment of IBD.
局部细胞外酸化与多种病症相关，如缺血、癌症、代谢性疾病、呼吸系统疾病及炎症性肠病（IBD）。近期多项研究报道了IBD与一类pH敏感型G蛋白偶联受体之间的联系。我们之前的研究表明OGR1（GPR68）在调节肠道炎症和纤维化中起关键作用。在本研究中，我们评估了一种新型OGR1抑制剂在小鼠结肠炎模型中的作用。
在急性和慢性葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中评估一种新型小分子OGR1抑制剂的作用。评估肠道炎症的宏观疾病指标，并通过免疫组织化学评估上皮损伤、免疫细胞浸润和增殖情况。
OGR1抑制剂改善了急性和慢性DSS诱导的结肠炎的临床参数。在用OGR1抑制剂治疗的小鼠中，内镜检查显示无增厚且血管正常，未检测到纤维蛋白。组织病理学结果显示，与载体-DSS对照组相比，OGR1抑制剂组结肠炎症的严重程度降低。在经OGR1抑制剂治疗的小鼠中，巨噬细胞标志物F4/80和细胞增殖标志物Ki-67的染色分别显示浸润巨噬细胞减少且细胞增殖略有增强。这伴随着促炎细胞因子TNF和IL-6以及纤维化标志物TGF-β1的减少。
这是第一份提供证据表明对OGR1进行药理抑制在小鼠结肠炎模型中有治疗作用的报告。我们的数据表明，使用特定小分子抑制剂靶向质子感应型OGR1可能是治疗IBD的一种新型治疗方法。
