CP-96,345, A SUBSTANCE-P ANTAGONIST, INHIBITS RAT INTESTINAL RESPONSES TO CLOSTRIDIUM-DIFFICILE TOXIN-A BUT NOT CHOLERA-TOXIN
CP-96,345, A SUBSTANCE-P ANTAGONIST, INHIBITS RAT INTESTINAL RESPONSES TO CLOSTRIDIUM-DIFFICILE TOXIN-A BUT NOT CHOLERA-TOXIN
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DOI：
10.1073/pnas.91.3.947
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发表时间：
1994-02-01
影响因子：
11.1
通讯作者：
LEEMAN, SE
中科院分区：
文献类型：
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作者：
POTHOULAKIS, C;CASTAGLIUOLO, I;LEEMAN, SE
艰难梭菌毒素A介导实验动物急性炎症性小肠结肠炎，而霍乱毒素引起非炎症性分泌性腹泻。本研究的目的是调查是否拮抗剂肽P物质，已知参与炎症反应的初级感觉神经元的组成部分，将抑制毒素A介导的肠炎在大鼠回肠。用P物质拮抗剂CP-96，345（2.5mg/kg体重）预处理大鼠，显著抑制A毒素暴露的回肠袢液体分泌（P < 0.01）和甘露醇渗透性（P < 0.01）。的保护作用，这是剂量依赖性的，引起了显着减少炎症的固有层，减少肠上皮细胞的坏死，并完全抑制毒素A介导的释放大鼠肥大细胞蛋白酶II，大鼠粘膜肥大细胞的特定产品。P物质拮抗剂CP-96，344的无活性对映体无作用。相比之下，CP-96，345预处理对将霍乱毒素施用到回肠袢中引起的肠道效应没有抑制作用。从这些数据中，我们得出结论，肽物质P参与毒素A的分泌和炎症效应，但不是霍乱毒素。
Toxin A from Clostridium difficile mediates acute inflammatory enterocolitis in experimental animals, while cholera toxin causes noninflammatory secretory diarrhea. The purpose of this study was to investigate whether an antagonist to the peptide substance P, a constituent of primary sensory neurons known to participate in inflammatory responses, would inhibit toxin A-mediated enteritis in the rat ileum. Pretreatment of rats with CP-96,345 (2.5 mg per kg of body weight), a substance P antagonist, dramatically inhibited fluid secretion (P < 0.01) and mannitol permeability (P < 0.01) in ileal loops exposed to toxin A. The protective effects, which were dose dependent, caused a significant reduction of inflammation in the lamina propria, reduction of the necrosis of intestinal epithelial cells, and complete inhibition of toxin A-mediated release of rat mast cell protease II, a specific product of rat mucosal mast cells. An inactive enantiomer of the substance P antagonist, CP-96,344, had no effect. In contrast, pretreatment with CP-96,345 had no inhibitory effect on the intestinal effects caused by administration of cholera toxin into the ileal loops. From these data, we conclude that the peptide substance P is involved in the secretory and inflammatory effects of toxin A but not of cholera toxin.