Disruption of the mucosal barrier during gut ischemia allows entry of digestive enzymes into the intestinal wall.
Disruption of the mucosal barrier during gut ischemia allows entry of digestive enzymes into the intestinal wall.
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DOI：
10.1097/shk.0b013e318240b59b
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Schmid-Schönbein GW
中科院分区：
文献类型：
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作者：
Chang M;Kistler EB;Schmid-Schönbein GW
肠缺血与高发病率和死亡率相关，但其潜在机制尚不清楚。我们推测，在缺血期间，肠粘膜屏障被破坏，允许消化酶进入肠壁启动自身消化。我们使用了大鼠内脏缺血模型，通过闭塞上级肠系膜和腹腔动脉长达30分钟，有和没有管腔注射氨甲环酸作为胰蛋白酶抑制剂。我们通过原位酶谱法确定了消化蛋白酶在肠切片上的位置和活性，并通过免疫组织化学和蛋白质印迹技术检查了粘膜屏障的两个组成部分的破坏：粘蛋白亚型以及E-钙粘蛋白的细胞外和细胞内结构域。结果表明，非缺血肠壁中蛋白酶活性水平较低。15分钟后，缺血蛋白酶活性在绒毛的尖端可见，30分钟后，增强的活性在整个肠壁厚度可见。这种活性伴随着粘蛋白层的破坏和E-钙粘蛋白的细胞内和细胞外结构域的损失。氨甲环酸抑制肠腔中的消化蛋白酶可减少形态学损伤和消化酶进入肠壁。这项研究表明，肠缺血几分钟内粘膜上皮屏障的破坏允许完全激活的胰腺消化蛋白酶穿过肠屏障进入，触发自身消化。
Intestinal ischemia is associated with high morbidity and mortality but the underlying mechanisms are uncertain. We hypothesize that during ischemia the intestinal mucosal barrier becomes disrupted, allowing digestive enzymes access into the intestinal wall initiating autodigestion. We used a rat model of splanchnic ischemia by occlusion of the superior mesenteric and celiac arteries up to 30 min with and without luminal injection of tranexamic acid as a trypsin inhibitor. We determined the location and activity of digestive proteases on intestinal sections with in-situ zymography and we examined the disruption of two components of the mucosal barrier: mucin isoforms and the extra- and intracellular domains of E-cadherin with immunohistochemistry and western blot techniques. The results indicate that non-ischemic intestine has low levels of protease activity in its wall. After 15 min ischemia protease activity was visible at the tip of the villi and after 30 min enhanced activity was seen across the full thickness of the intestinal wall. This activity was accompanied by disruption of the mucin layer and loss of both intra- and extracellular domains of E-cadherin. Digestive protease inhibition in the intestinal lumen with tranexamic acid reduced morphological damage and entry of digestive enzymes into the intestinal wall. This study demonstrates that disruption of the mucosal epithelial barrier within minutes of intestinal ischemia allows entry of fully activated pancreatic digestive proteases across the intestinal barrier triggering autodigestion.