Dept. of Gastroenterology, Affiliated Hospital, Zunyi Medical College, Dalian Rd. 149, Zunyi 563003, China.
Am J Physiol Gastrointest Liver Physiol. 2012 Dec 15;303(12):G1312-21. doi: 10.1152/ajpgi.00035.2012. Epub 2012 Sep 27.
The incidence of duodenal ulcer, especially Helicobacter pylori-negative duodenal ulcer, strongly increases with age. In humans, telomere length shortening is considered to be one critical factor in cellular senescence and organ survival. In this study, we compared basal and stimulated gastric acid and duodenal HCO(3)(-) secretory rates in aged late-generation (G(3)) telomerase-deficient (mTERC(-/-)) mice, which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division. We found that basal and forskolin-stimulated HCO(3)(-) secretion and short-circuit current (I(sc)) in isolated duodenal mucosa of G(3) mTERC(-/-) mice were markedly reduced compared with age-matched wild-type mice. In contrast, basal and forskolin-stimulated acid secretory rates in isolated G(3) mTERC(-/-) gastric mucosa were not significantly altered. Correspondingly, duodenal mucosa of G(3) mTERC(-/-) mice showed slimming and shortening of villi, whereas gastric mucosal histology was not significantly altered. However, the ratios of cystic fibrosis transmembrane conductance regulator (CFTR) and solute-linked carrier 26 gene family (Slc26a6) mRNA expression in relation to cytokeratin-18 were not altered in duodenal mucosa. The further knockout of p21, which is a downstream effector of telomere shortening-induced senescence, rescued villus atrophy of duodenal mucosa, and basal and forskolin-stimulated duodenal HCO(3)(-) secretion and I(sc) in mTERC(-/-) p21(-/-) double-knockout mice were not different from wild-type controls. In conclusion, genetic ablation of telomerase resulted in p21-dependent duodenal mucosal atrophy and reduced duodenal HCO(3)(-) secretory capacity, whereas gastric morphology and acid secretory function were preserved. This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation.
十二指肠溃疡的发病率，尤其是幽门螺杆菌阴性的十二指肠溃疡，随着年龄的增长而强烈增加。在人类中，端粒缩短被认为是细胞衰老和器官存活的一个关键因素。在这项研究中，我们比较了高龄第三代（G3）端粒酶缺陷（mTERC(-/-)）小鼠的基础和刺激胃酸以及十二指肠 HCO(3)(-)分泌率，这些小鼠由于在细胞分裂过程中无法延长端粒而导致端粒功能严重障碍。我们发现，与年龄匹配的野生型小鼠相比，G3 mTERC(-/-)小鼠分离的十二指肠黏膜的基础和福司可林刺激的 HCO(3)(-)分泌和短路电流（I(sc)）明显降低。相比之下，G3 mTERC(-/-)胃黏膜的基础和福司可林刺激的胃酸分泌率没有明显改变。相应地，G3 mTERC(-/-)小鼠的十二指肠黏膜出现萎缩和绒毛缩短，而胃黏膜组织学没有明显改变。然而，囊性纤维化跨膜电导调节体（CFTR）和溶质载体 26 基因家族（Slc26a6）mRNA 与细胞角蛋白-18 的比值在十二指肠黏膜中没有改变。p21 的进一步敲除，p21 是端粒缩短诱导衰老的下游效应物，挽救了 mTERC(-/-) p21(-/-)双敲除小鼠的十二指肠黏膜绒毛萎缩，并且 mTERC(-/-) p21(-/-)双敲除小鼠的基础和福司可林刺激的十二指肠 HCO(3)(-)分泌和 I(sc)与野生型对照组没有差异。总之，端粒酶的基因缺失导致 p21 依赖性十二指肠黏膜萎缩和十二指肠 HCO(3)(-)分泌能力降低，而胃形态和胃酸分泌功能保持不变。这表明，衰老过程中端粒缩短可能导致十二指肠黏膜的侵袭性和保护性分泌之间失衡，从而易患溃疡形成。
