通过抑制pH感应受体GPR4治疗肠道纤维化的新方法

New Therapeutic Approach for Intestinal Fibrosis Through Inhibition of pH-Sensing Receptor GPR4.

作者信息

Weder Bruce, Schefer Fabian, van Haaften Wouter Tobias, Patsenker Eleonora, Stickel Felix, Mueller Sebastian, Hutter Senta, Schuler Cordelia, Baebler Katharina, Wang Yu, Mamie Céline, Dijkstra Gerard, de Vallière Cheryl, Imenez Silva Pedro H, Wagner Carsten A, Frey-Wagner Isabelle, Ruiz Pedro A, Seuwen Klaus, Rogler Gerhard, Hausmann Martin

机构信息

Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.

Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

出版信息

Inflamm Bowel Dis. 2022 Jan 5;28(1):109-125. doi: 10.1093/ibd/izab140.

DOI:10.1093/ibd/izab140

PMID:34320209

Abstract

BACKGROUND

Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of pH-sensing receptors compared with non-IBD controls. Acidification leads to angiogenesis and extracellular matrix remodeling. We aimed to determine the expression of pH-sensing G protein-coupled receptor 4 (GPR4) in fibrotic lesions in Crohn's disease (CD) patients. We further evaluated the effect of deficiency in Gpr4 or its pharmacologic inhibition.

METHODS

Paired samples from fibrotic and nonfibrotic terminal ileum were obtained from CD patients undergoing ileocaecal resection. The effects of Gpr4 deficiency were assessed in the spontaneous Il-10-/- and the chronic dextran sodium sulfate (DSS) murine colitis model. The effects of Gpr4 deficiency and a GPR4 antagonist (39c) were assessed in the heterotopic intestinal transplantation model.

RESULTS

In human terminal ileum, increased expression of fibrosis markers was accompanied by an increase in GPR4 expression. A positive correlation between the expression of procollagens and GPR4 was observed. In murine disease models, Gpr4 deficiency was associated with a decrease in angiogenesis and fibrogenesis evidenced by decreased vessel length and expression of Edn, Vegfα, and procollagens. The heterotopic animal model for intestinal fibrosis, transplanted with terminal ileum from Gpr4-/- mice, revealed a decrease in mRNA expression of fibrosis markers and a decrease in collagen content and layer thickness compared with grafts from wild type mice. The GPR4 antagonist decreased collagen deposition. The GPR4 expression was also observed in human and murine intestinal fibroblasts. The GPR4 inhibition reduced markers of fibroblast activation stimulated by low pH, notably Acta2 and cTgf.

CONCLUSIONS

Expression of GPR4 positively correlates with the expression of profibrotic genes and collagen. Deficiency of Gpr4 is associated with a decrease in angiogenesis and fibrogenesis. The GPR4 antagonist decreases collagen deposition. Targeting GPR4 with specific inhibitors may constitute a new treatment option for IBD-associated fibrosis.

摘要

背景

与非炎症性肠病（IBD）对照相比，患有IBD的患者黏膜中pH感应受体水平升高。酸化会导致血管生成和细胞外基质重塑。我们旨在确定pH感应G蛋白偶联受体4（GPR4）在克罗恩病（CD）患者纤维化病变中的表达。我们进一步评估了Gpr4缺乏或其药物抑制的作用。

方法

从接受回盲部切除术的CD患者获取纤维化和非纤维化回肠末端的配对样本。在自发性Il-10-/-和慢性葡聚糖硫酸钠（DSS）小鼠结肠炎模型中评估Gpr4缺乏的影响。在异位肠道移植模型中评估Gpr4缺乏和GPR4拮抗剂（39c）的作用。

结果

在人类回肠末端，纤维化标志物表达增加伴随着GPR4表达增加。观察到前胶原表达与GPR4之间呈正相关。在小鼠疾病模型中，Gpr4缺乏与血管生成和纤维化形成减少有关，表现为血管长度以及内皮素、血管内皮生长因子α（Vegfα）和前胶原表达降低。用Gpr4-/-小鼠回肠末端进行移植的肠道纤维化异位动物模型显示，与野生型小鼠的移植物相比，纤维化标志物的mRNA表达降低，胶原含量和层厚度减少。GPR4拮抗剂减少了胶原沉积。在人和小鼠肠道成纤维细胞中也观察到GPR4表达。GPR4抑制降低了低pH刺激的成纤维细胞活化标志物，特别是平滑肌肌动蛋白（Acta2）和结缔组织生长因子（cTgf）。