Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland.
Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
J Crohns Colitis. 2018 Nov 15;12(11):1348-1358. doi: 10.1093/ecco-jcc/jjy118.
pH-sensing ovarian cancer G-protein coupled receptor-1 [OGR1/GPR68] is regulated by key inflammatory cytokines. Patients suffering from inflammatory bowel diseases [IBDs] express increased mucosal levels of OGR1 compared with non-IBD controls. pH-sensing may be relevant for progression of fibrosis, as extracellular acidification leads to fibroblast activation and extracellular matrix remodelling. We aimed to determine OGR1 expression in fibrotic lesions in the intestine of Crohn's disease [CD] patients, and the effect of Ogr1 deficiency in fibrogenesis.
Human fibrotic and non-fibrotic terminal ileum was obtained from CD patients undergoing ileocaecal resection due to stenosis. Gene expression of fibrosis markers and pH-sensing receptors was analysed. For the initiation of fibrosis in vivo, spontaneous colitis by Il10-/-, dextran sodium sulfate [DSS]-induced chronic colitis and the heterotopic intestinal transplantation model were used.
Increased expression of fibrosis markers was accompanied by an increase in OGR1 [2.71 ± 0.69 vs 1.18 ± 0.03, p = 0.016] in fibrosis-affected human terminal ileum, compared with the non-fibrotic resection margin. Positive correlation between OGR1 expression and pro-fibrotic cytokines [TGFB1 and CTGF] and pro-collagens was observed. The heterotopic animal model for intestinal fibrosis transplanted with terminal ileum from Ogr1-/- mice showed a decrease in mRNA expression of fibrosis markers as well as a decrease in collagen layer thickness and hydroxyproline compared with grafts from wild-type mice.
OGR1 expression was correlated with increased expression levels of pro-fibrotic genes and collagen deposition. Ogr1 deficiency was associated with a decrease in fibrosis formation. Targeting OGR1 may be a potential new treatment option for IBD-associated fibrosis.
pH 感应卵巢癌 G 蛋白偶联受体-1 [OGR1/GPR68] 受关键炎症细胞因子调节。与非 IBD 对照相比，患有炎症性肠病 [IBD] 的患者表达增加的黏膜 OGR1 水平。pH 感应可能与纤维化的进展有关，因为细胞外酸化导致成纤维细胞活化和细胞外基质重塑。我们旨在确定克罗恩病 [CD] 患者肠道纤维化病变中的 OGR1 表达，以及 Ogr1 缺乏对纤维化形成的影响。
从因狭窄而行回肠末端切除术的 CD 患者中获得纤维化和非纤维化的末端回肠。分析纤维化标志物和 pH 感应受体的基因表达。为了在体内启动纤维化，使用 Il10-/-、葡聚糖硫酸钠 [DSS]-诱导的慢性结肠炎和异位肠移植模型诱导自发性结肠炎。
与非纤维化的切除边缘相比，纤维化受累的人末端回肠中纤维化标志物的表达增加伴随着 OGR1 [2.71 ± 0.69 比 1.18 ± 0.03，p = 0.016] 的增加。观察到 OGR1 表达与促纤维化细胞因子 [TGFB1 和 CTGF] 和前胶原呈正相关。与野生型小鼠移植的末端回肠相比，从 Ogr1-/- 小鼠移植的用于肠道纤维化的异位动物模型显示纤维化标志物的 mRNA 表达减少，胶原层厚度和羟脯氨酸减少。
OGR1 的表达与促纤维化基因和胶原蛋白沉积的表达水平增加相关。Ogr1 缺乏与纤维化形成减少有关。靶向 OGR1 可能是治疗 IBD 相关纤维化的新潜在治疗选择。
