Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
Am J Gastroenterol. 2010 Sep;105(9):1934-43. doi: 10.1038/ajg.2010.265. Epub 2010 Jun 29.
The proteinase-activated receptor-2 (PAR-2) is activated by serine proteases and has been demonstrated to induce proinflammatory and neuroinflammatory effects. It is considered to alter transepithelial resistance and mediates visceral hypersensitivity. This study aimed to evaluate the expression of PAR-2 in human esophageal mucosa of patients with gastroesophageal reflux disease (GERD) in relation to mucosal alterations.
The study included 123 patients with GERD stratified to erosive reflux disease (n=50), non-erosive reflux disease (n=46), and reflux-negative patients as controls (n=27). Endoscopic and histopathological characterization was performed according to the Los Angeles classification and modified Ismail-Beigi criteria, respectively. PAR-2 expression was analyzed by quantitative reverse transcription (RT)-PCR and immunohistochemistry. The gene expression levels of interleukin (IL)-8 were determined by quantitative RT-PCR and correlated to PAR-2 expression in each patient. Performing in vitro studies, esophageal squamous cell lines (KYSE 150, KYSE 450) were incubated, adjusted to different pH (7.0, 6.0, and 5.0), and exposed to bile acids and PAR-2-activation peptide (SLIGKV-NH(2)).
PAR-2 gene expression was 7- to 10-fold upregulated (P<0.0001) in the mucosa of patients with GERD and correlated positively with IL-8 expression and with histomorphological alterations (dilated intercellular spaces, papillary elongation, basal cell hyperplasia (BCH); P<0.01). Immunohistochemistry showed an intense staining of PAR-2 throughout all epithelial layers in patients with GERD compared with controls (P=0.0005). In vitro studies revealed a 1.5- to 20-fold induction of PAR-2 gene expression in esophageal squamous cells by acidified medium (P<0.01), but not by additional bile acids. The activation of PAR-2 leads to expression and secretion of IL-8.
This study provides evidence of the functional importance of PAR-2-mediated pathways in the pathogenesis of GERD and GERD-associated mucosal alterations and inflammatory changes.
蛋白酶激活受体-2（PAR-2）可被丝氨酸蛋白酶激活，已被证实可诱导促炎和神经炎症反应。它被认为可以改变上皮细胞间的通透性，并介导内脏敏感性。本研究旨在评估 PAR-2 在胃食管反流病（GERD）患者食管黏膜中的表达与黏膜改变的关系。
本研究纳入了 123 例 GERD 患者，根据洛杉矶分类标准分为糜烂性反流病（n=50）、非糜烂性反流病（n=46）和反流阴性对照组（n=27）。根据洛杉矶分类标准和改良的 Ismail-Beigi 标准进行内镜和组织病理学特征分析。通过定量逆转录（RT）-PCR 和免疫组织化学分析 PAR-2 的表达。通过定量 RT-PCR 测定白细胞介素（IL）-8 的基因表达水平，并与每位患者的 PAR-2 表达相关联。进行体外研究，将食管鳞状细胞系（KYSE 150、KYSE 450）孵育，调整至不同 pH 值（7.0、6.0 和 5.0），并暴露于胆汁酸和 PAR-2 激活肽（SLIGKV-NH₂）。
GERD 患者的黏膜中 PAR-2 基因表达上调了 7-10 倍（P<0.0001），与 IL-8 表达和组织形态学改变（细胞间隙扩张、乳头伸长、基底细胞增生（BCH）呈正相关（P<0.01）。与对照组相比，免疫组织化学显示 GERD 患者的整个上皮层均有强烈的 PAR-2 染色（P=0.0005）。体外研究显示，酸化介质可使食管鳞状细胞的 PAR-2 基因表达上调 1.5-20 倍（P<0.01），但胆汁酸无此作用。PAR-2 的激活导致 IL-8 的表达和分泌。
本研究提供了证据表明，PAR-2 介导的途径在 GERD 的发病机制以及 GERD 相关的黏膜改变和炎症变化中具有重要功能。
