Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin-18 downregulation and acid backflux.
Genetic ablation of carbonic anhydrase IX disrupts gastric barrier function via claudin-18 downregulation and acid backflux.
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碳酸酐酶 IX 的基因消除通过claudin-18下调和酸反流破坏胃屏障功能
DOI：
10.1111/apha.12923
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Seidler U
中科院分区：
文献类型：
--
作者：
Li T;Liu X;Riederer B;Nikolovska K;Singh AK;Mäkelä KA;Seidler A;Liu Y;Gros G;Bartels H;Herzig KH;Seidler U
本研究旨在探讨碳酸酐酶9（CAIX）缺失小鼠胃粘膜壁细胞丢失和胃底增生的分子机制。我们通过使用双光子共聚焦激光扫描显微镜在体内测量外置胃粘膜的pH i来评估CAIX敲除和WT胃表面上皮细胞耐受管腔酸负荷的能力。通过RT-PCR分析细胞因子和claudin-18 A2表达。 与WT相比，CAIX敲除胃表面上皮细胞在腔酸负荷后显示出明显更快的pH下降速度。断奶后不久，在壁细胞和主细胞丢失之前，观察到胃粘膜IL-1β和iNOS增加，但claudin-18 A2表达减少（这赋予了酸抗性）。出生时，CAIX和WT胃粘膜之间的炎性细胞因子和claudin-18表达均未改变。酸分泌能力的逐渐丧失被血清胃泌素、IL-11和小凹增生的增加所掩盖。从断奶时开始的轻度慢性质子泵抑制并不能阻止1月龄时claudin-18的减少，也不能阻止炎症标志物的增加，除了IL-1β。然而，在随后的几个月里，治疗减少了CAIX‐KO小鼠的壁细胞损失。我们建议CAIX将质子快速地从细胞中回流或挤出为CO2和H2O，从而有助于紧密连接保护和胃上皮pH i调节。缺乏CAIX通过claudin-18下调导致持续的酸回流，导致壁细胞损失、高胃泌素血症和小凹增生。
This study aimed to explore the molecular mechanisms for the parietal cell loss and fundic hyperplasia observed in gastric mucosa of mice lacking the carbonic anhydrase 9 (CAIX). We assessed the ability of CAIX‐knockout and WT gastric surface epithelial cells to withstand a luminal acid load by measuring the pH i of exteriorized gastric mucosa in vivo using two‐photon confocal laser scanning microscopy. Cytokines and claudin‐18A2 expression was analysed by RT‐PCR. CAIX‐knockout gastric surface epithelial cells showed significantly faster pH i decline after luminal acid load compared to WT. Increased gastric mucosal IL‐1β and iNOS, but decreased claudin‐18A2 expression (which confer acid resistance) was observed shortly after weaning, prior to the loss of parietal and chief cells. At birth, neither inflammatory cytokines nor claudin‐18 expression were altered between CAIX and WT gastric mucosa. The gradual loss of acid secretory capacity was paralleled by an increase in serum gastrin, IL‐11 and foveolar hyperplasia. Mild chronic proton pump inhibition from the time of weaning did not prevent the claudin‐18 decrease nor the increase in inflammatory markers at 1 month of age, except for IL‐1β. However, the treatment reduced the parietal cell loss in CAIX‐KO mice in the subsequent months. We propose that CAIX converts protons that either backflux or are extruded from the cells rapidly to CO 2 and H2O, contributing to tight junction protection and gastric epithelial pH i regulation. Lack of CAIX results in persistent acid backflux via claudin‐18 downregulation, causing loss of parietal cells, hypergastrinaemia and foveolar hyperplasia.
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影响因子：
29.4
作者：
Friis-Hansen, Lennart;Rieneck, Klaus;Rehfeld, Jens F.
通讯作者：
Rehfeld, Jens F.
DOI：
10.1152/ajpgi.00187.2006
发表时间：
2006-12-01
影响因子：
4.5
作者：
Goldenring, James R.;Nomura, Sachiyo
通讯作者：
Nomura, Sachiyo
DOI：
10.1073/pnas.0508007102
发表时间：
2005-10-18
影响因子：
11.1
作者：
Leppilampi, M;Parkkila, S;Sjöblom, M
通讯作者：
Sjöblom, M
影响因子：
24.5
作者：
Howlett M;Chalinor HV;Buzzelli JN;Nguyen N;van Driel IR;Bell KM;Fox JG;Dimitriadis E;Menheniott TR;Giraud AS;Judd LM
通讯作者：
Judd LM
DOI：
10.1111/j.1440-1746.2005.03867.x
发表时间：
2005-08-01
影响因子：
4.1
作者：
Judd, LM;Andringa, A;Miller, ML
通讯作者：
Miller, ML