Pothoulakis C, Karmeli F, Kelly C P, Eliakim R, Joshi M A, O'Keane C J, Castagliuolo I, LaMont J T, Rachmilewitz D
Section of Gastroenterology, University Hospital, Boston University School of Medicine, Massachusetts.
Gastroenterology. 1993 Sep;105(3):701-7. doi: 10.1016/0016-5085(93)90886-h.
Clostridium difficile toxin A is the principal mediator of inflammatory enterocolitis in experimental animals. The purpose of this study was to explore the effect of ketotifen, an anti-inflammatory drug, on toxin A-induced enterotoxicity in rat ileum.
The effects of intragastric administration of ketotifen on secretion, mannitol permeability, histological damage, and mucosal levels of leukotriene B4, leukotriene C4, and platelet activating factor in toxin A-exposed rat ileal loops were measured in vivo. The effects of ketotifen on toxin A-mediated release of rat mast cell protease II (rat mucosa mast cell product) release were also measured in rat ileal explants in vitro. The effect of ketotifen on neutrophil migration in vitro was also evaluated.
Ketotifen pretreatment inhibited toxin A-associated intestinal secretion by 42.5% and mannitol permeability by 56.3% and reduced epithelial cell inflammation and necrosis. These effects were associated with reduced levels of leukotriene B4 by 65.8%, leukotriene C4 by 88.8%, platelet activating factor by 77.8%, and inhibition of rat mast cell protease II by 58.4%. In addition, pretreatment of neutrophils with ketotifen inhibited neutrophil migration in vitro.
The protective effect of ketotifen in this animal model was associated with significant inhibition of release of mast cells and neutrophil derived mediators, supporting their involvement in C. difficile enteritis.
艰难梭菌毒素A是实验动物炎症性小肠结肠炎的主要介质。本研究的目的是探讨抗炎药物酮替芬对毒素A诱导的大鼠回肠肠毒性的影响。
在体内测量胃内给予酮替芬对毒素A暴露的大鼠回肠肠袢中分泌、甘露醇通透性、组织学损伤以及白三烯B4、白三烯C4和血小板活化因子黏膜水平的影响。在体外大鼠回肠外植体中也测量了酮替芬对毒素A介导的大鼠肥大细胞蛋白酶II（大鼠黏膜肥大细胞产物）释放的影响。还评估了酮替芬在体外对中性粒细胞迁移的影响。
酮替芬预处理可使毒素A相关的肠道分泌减少42.5%，甘露醇通透性降低56.3%，并减轻上皮细胞炎症和坏死。这些作用与白三烯B4水平降低65.8%、白三烯C4降低88.8%、血小板活化因子降低77.8%以及大鼠肥大细胞蛋白酶II抑制58.4%相关。此外，用酮替芬预处理中性粒细胞可抑制其在体外的迁移。
在该动物模型中，酮替芬的保护作用与显著抑制肥大细胞和中性粒细胞衍生介质的释放有关，支持它们参与艰难梭菌肠炎。
