Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock.
Pancreatic digestive enzyme blockade in the intestine increases survival after experimental shock.
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DOI：
10.1126/scitranslmed.3005046
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发表时间：
2013-01-23
影响因子：
17.1
通讯作者：
Schmid-Schönbein GW
中科院分区：
文献类型：
--
作者：
DeLano FA;Hoyt DB;Schmid-Schönbein GW
休克、败血症和多器官衰竭与炎症、发病率和高死亡率相关。其潜在的病理生理学机制尚不清楚，但有证据表明肠腔内的胰腺酶自消化肠道并产生全身性炎症。在肠道中阻断这些酶可以减少炎症和多器官功能障碍。我们研究了酶阻断是否也能降低休克后的死亡率。本研究采用三种大鼠休克模型：失血性休克、盲肠材料置入腹膜引起的腹膜炎休克和内毒素休克。在出血、腹膜炎或内毒素休克开始后1小时，将三种不同的胰腺酶抑制剂之一-6-脒基-2-萘基对胍基苯甲酸酯二甲烷硫酸盐、氨甲环酸或抑肽酶-给予动物的小肠腔内。在所有形式的休克中，用蛋白酶抑制剂阻断消化蛋白酶可减弱消化酶进入肠壁以及随后的自身消化和对肠、肺和心脏的形态学损伤。在12周的时间内，用蛋白酶抑制剂处理的动物也比未处理的对照组存活更多。存活的动物在休克后14天内完全恢复并恢复正常体重。结果表明，肠腔中活性和浓缩的消化酶在休克和多器官衰竭中起着核心作用，这可以用目前临床上可用的蛋白酶抑制剂来治疗。
Shock, sepsis, and multiorgan failure are associated with inflammation, morbidity, and high mortality. The underlying pathophysiological mechanism is unknown, but evidence suggests that pancreatic enzymes in the intestinal lumen autodigest the intestine and generate systemic inflammation. Blocking these enzymes in the intestine reduces inflammation and multiorgan dysfunction. We investigated whether enzymatic blockade also reduces mortality after shock. Three rat shock models were used here: hemorrhagic shock, peritonitis shock induced by placement of cecal material into the peritoneum, and endotoxin shock. One hour after initiation of hemorrhagic, peritonitis, or endotoxin shock, animals were administered one of three different pancreatic enzyme inhibitors—6-amidino-2-naphtyl p-guanidinobenzoate di-methanesulfate, tranexamic acid, or aprotinin—into the lumen of the small intestine. In all forms of shock, blockade of digestive proteases with protease inhibitor attenuated entry of digestive enzymes into the wall of the intestine and subsequent autodigestion and morphological damage to the intestine, lung, and heart. Animals treated with protease inhibitors also survived in larger numbers than untreated controls over a period of 12 weeks. Surviving animals recovered completely and returned to normal weight within 14 days after shock. The results suggest that the active and concentrated digestive enzymes in the lumen of the intestine play a central role in shock and multi-organ failure, which can be treated with protease inhibitors that are currently available for use in the clinic.