van Roon Aafke H C, Mayne George C, Wijnhoven Bas P L, Watson David I, Leong Mary P, Neijman Gabriëlle E, Michael Michael Z, McKay Andrew R, Astill David, Hussey Damian J
Department of Surgery, Flinders Medical Centre, Flinders University, Room 3D211, Bedford Park, South Australia, 5042, Australia.
J Gastrointest Surg. 2008 Aug;12(8):1331-40. doi: 10.1007/s11605-008-0522-y. Epub 2008 May 2.
Changes in the expression of mucin genes in the esophageal mucosa associated with uncomplicated gastro-esophageal reflux disease have not been evaluated even though such changes could be associated with reflux-induced mucosal damage. We therefore sought to identify reflux-induced changes in mucin gene expression using a cell line and biopsies from the esophageal mucosa in patients with and without reflux.
MUC-1, MUC-3, MUC-4, and MUC-5AC gene expressions were investigated in the HET-1A cell line following exposure to acid (pH 4) and/or bile (120 muM of a bile salt milieu), and in esophageal mucosal biopsies from controls, subjects with non-erosive gastro-esophageal reflux, and subjects with reflux associated with ulcerative esophagitis (erosive). The mucosal biopsies were also evaluated for IL-6 mRNA expression (inflammatory marker) and CK-14 mRNA expression (mucosal basal cell layer marker). Gene expression was determined using real-time reverse transcriptase-polymerase chain reaction analysis.
In the cell line studies, there were differences in mRNA levels for all of the evaluated mucins following treatment with either acid or the acid and bile combination. In the studies which evaluated tissue specimens, IL-6 and CK-14 mRNA levels increased according to degree of reflux pathology. The expression of MUC-1 and MUC-4 in mucosa from patients with erosive reflux was lower than in subjects without reflux and in patients with non-erosive reflux, whereas the expression of MUC-3 and MUC-5AC was increased (although these differences did not reach significance at p < 0.05). When mRNA expression data for tissue samples from all groups were combined, significant correlations were identified between IL-6 vs. CK-14 and IL-6 vs. MUC-3, MUC-3 vs. CK-14 and MUC-3 vs. MUC-5AC, and for MUC-1 vs. MUC-5AC. The correlation between IL-6 and CK-14 was also significant within the control and non-erosive reflux groups. The correlation between IL-6 and MUC-3 was significant within the control and erosive reflux groups, and the correlation between MUC-1 and MUC-5AC was significant within the erosive reflux group.
The results of this study suggest that the profile of mucin expression in the esophageal mucosa is influenced by the pH and composition of the gastro-esophageal reflux. Further work should explore the response of these genes to acid and bile reflux, and their role in the etiology of mucosal damage in gastro-esophageal reflux.
尽管与单纯性胃食管反流病相关的食管黏膜黏蛋白基因表达变化可能与反流引起的黏膜损伤有关，但尚未得到评估。因此，我们试图使用细胞系以及有反流和无反流患者的食管黏膜活检来确定反流引起的黏蛋白基因表达变化。
在HET-1A细胞系中，研究暴露于酸（pH 4）和/或胆汁（120 μM胆盐环境）后MUC-1、MUC-3、MUC-4和MUC-5AC基因的表达情况，并在对照组、非糜烂性胃食管反流患者以及与溃疡性食管炎（糜烂性）相关的反流患者的食管黏膜活检组织中进行研究。还对黏膜活检组织进行了IL-6 mRNA表达（炎症标志物）和CK-14 mRNA表达（黏膜基底细胞层标志物）的评估。使用实时逆转录聚合酶链反应分析来确定基因表达。
在细胞系研究中，用酸或酸与胆汁联合处理后，所有评估的黏蛋白的mRNA水平均存在差异。在评估组织标本的研究中，IL-6和CK-14 mRNA水平根据反流病理程度而升高。糜烂性反流患者黏膜中MUC-1和MUC-4的表达低于无反流患者和非糜烂性反流患者，而MUC-3和MUC-5AC的表达增加（尽管这些差异在p < 0.05时未达到显著水平）。当合并所有组组织样本的mRNA表达数据时，发现IL-6与CK-14、IL-6与MUC-3、MUC-3与CK-14、MUC-3与MUC-5AC以及MUC-1与MUC-5AC之间存在显著相关性。在对照组和非糜烂性反流组中，IL-6与CK-14之间的相关性也很显著。在对照组和糜烂性反流组中，IL-6与MUC-3之间的相关性显著，在糜烂性反流组中，MUC-1与MUC-5AC之间的相关性显著。
本研究结果表明，食管黏膜中黏蛋白的表达谱受胃食管反流的pH值和成分影响。进一步的研究应探索这些基因对酸和胆汁反流的反应及其在胃食管反流黏膜损伤病因学中的作用。
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