Leppilampi Mari, Parkkila Seppo, Karttunen Tuomo, Gut Marta Ortova, Gros Gerolf, Sjöblom Markus
Institute of Medical Technology, University of Tampere and Tampere University Hospital, FI-33520 Tampere, Finland.
Proc Natl Acad Sci U S A. 2005 Oct 18;102(42):15247-52. doi: 10.1073/pnas.0508007102. Epub 2005 Oct 10.
Duodenal bicarbonate secretion (DBS) is accepted as the primary mucosal defense against acid discharged from the stomach and is impaired in patients with duodenal ulcer disease. The secretory response to luminal acid is the main physiological stimulus for DBS and involves mediation by PGE2 produced by mucosal cells. The aim of this investigation is to elucidate the role of carbonic anhydrases (CAs) II and IX in PGE2-mediated bicarbonate secretion in the murine duodenum. CA II- and IX-deficient mice and different combinations of their heterozygous and WT counterparts were studied. A 10-mm segment of the proximal duodenum with intact blood supply was isolated, and DBS was titrated by pH-stat (TitroLine-easy, Schott, Mainz, Germany). Mean arterial blood pressure (MAP) was continuously recorded, and blood acid/base balance and gastrointestinal morphology were analyzed. The duodenal segment spontaneously secreted HCO3(-) at a steady basal rate of 5.3 +/- 0.6 micromol x cm(-1) x h(-1). Perfusing the duodenal lumen for 20 min with 47 microM PGE2 caused a significant increase in DBS to 13.0 +/- 2.9 micromol x cm(-1) x h(-1), P < 0.0001. The DBS response to PGE2 was completely absent in Car2-/- mice, whereas basal DBS was normal. The CA IX-deficient mice with normal Car2 alleles showed a slight increase in DBS. Histological abnormalities were observed in the gastroduodenal epithelium in both CA II- and IX-deficient mice. Our data demonstrate a gastrointestinal phenotypic abnormality associated with CA II deficiency. The results show that the stimulatory effect of the duodenal secretagogue PGE2 completely depends on CA II.
十二指肠碳酸氢盐分泌（DBS）被认为是抵御胃排出的酸的主要黏膜防御机制，十二指肠溃疡病患者的该机制受损。对腔内酸的分泌反应是DBS的主要生理刺激因素，涉及黏膜细胞产生的前列腺素E2（PGE2）介导。本研究的目的是阐明碳酸酐酶（CAs）II和IX在小鼠十二指肠PGE2介导的碳酸氢盐分泌中的作用。研究了CA II和IX基因敲除小鼠及其杂合子和野生型对应物的不同组合。分离出一段近端十二指肠，长度为10毫米，血供完整，并用pH计（TitroLine-easy，肖特公司，美因茨，德国）滴定DBS。连续记录平均动脉血压（MAP），并分析血液酸碱平衡和胃肠道形态。十二指肠段以5.3±0.6微摩尔×厘米-1×小时-1的稳定基础速率自发分泌HCO3-。用47微摩尔的PGE2灌注十二指肠腔20分钟导致DBS显著增加至13.0±2.9微摩尔×厘米-1×小时-1，P<0.0001。在Car2-/-小鼠中，对PGE2的DBS反应完全缺失，而基础DBS正常。具有正常Car2等位基因的CA IX基因敲除小鼠的DBS略有增加。在CA II和IX基因敲除小鼠的胃十二指肠上皮中均观察到组织学异常。我们的数据表明与CA II缺乏相关的胃肠道表型异常。结果表明，十二指肠促分泌素PGE2的刺激作用完全依赖于CA II。
