Carneiro-Filho B A, Souza M L, Lima A A, Ribeiro R A
Department of Physiology and Pharmacology, University Hospital, Faculty of Medicine, Federal University of Ceara, Brazil.
Pharmacol Toxicol. 2001 Jun;88(6):313-8.
Clostridium difficile produces a potent enterotoxin and a cytotoxin, toxin A and toxin B, respectively. These toxins are associated with pseudomembranous colitis and antibiotic-associated diarrhoea. In the present study, we investigated the oedematogenic activity of both toxins, characterizing the time-course and dose-response of this pro-inflammatory event. We also explored the effects of two inhibitors of tumour necrosis factor (TNF) production, thalidomide and pentoxifylline, in neutrophil recruitment and the oedematogenic activity of these toxins. Subplantar injection of toxin A induced paw oedema with a maximal response at 1 microg, reaching a maximal value 9 hr after toxin A challenge (toxin A 1 microg:1.39+/-0.09 ml). Toxin B also showed a dose-dependent oedematogenic activity with a late peak at 24 hr and a maximal response at a dose of 0.1 microg (toxin B 0.1 microg:1.74+/-0.12 ml). Pentoxifylline, but not thalidomide, significantly reduced the oedema induced by Toxin A (pentoxifylline 135 mg/kg:60% of inhibition) and Toxin B (pentoxifylline 135 mg/kg:33.6% of inhibition). Both thalidomide and pentoxifylline were able to significantly reduce neutrophil influx into the peritoneal cavities of rats evoked with Toxin A (thalidomide 45 mg/kg: 53.1% of inhibition; pentoxifylline 45 mg/kg:47.1% of inhibition) and Toxin B (thalidomide 45 mg/kg:46.8% of inhibition; pentoxifylline 45 mg/kg:63.1% of inhibition). This study demonstrates the oedematogenic activities of both toxins with distinct potencies and time-courses. These data also show an inhibitory effect of pentoxifylline in toxin A and B-induced paw oedema. Furthermore, both pentoxifylline and thalidomide significantly inhibited the Clostridium difficile toxins-induced neutrophil migration.
艰难梭菌分别产生一种强效肠毒素和一种细胞毒素，即毒素A和毒素B。这些毒素与伪膜性结肠炎和抗生素相关性腹泻有关。在本研究中，我们研究了两种毒素的致水肿活性，表征了这一促炎事件的时间进程和剂量反应。我们还探讨了两种肿瘤坏死因子（TNF）产生抑制剂沙利度胺和己酮可可碱对中性粒细胞募集以及这些毒素致水肿活性的影响。足底注射毒素A可诱导爪部水肿，在1微克时出现最大反应，在毒素A激发后9小时达到最大值（毒素A 1微克：1.39±0.09毫升）。毒素B也表现出剂量依赖性的致水肿活性，在24小时出现晚期峰值，在0.1微克剂量时出现最大反应（毒素B 0.1微克：1.74±0.12毫升）。己酮可可碱而非沙利度胺能显著减轻毒素A（己酮可可碱135毫克/千克：60%的抑制率）和毒素B（己酮可可碱135毫克/千克：33.6%的抑制率）诱导的水肿。沙利度胺和己酮可可碱均能显著减少毒素A（沙利度胺45毫克/千克：53.1%的抑制率；己酮可可碱45毫克/千克：47.1%的抑制率）和毒素B（沙利度胺45毫克/千克：46.8%的抑制率；己酮可可碱45毫克/千克：63.1%的抑制率）诱发的大鼠腹腔内中性粒细胞流入。本研究证明了两种毒素具有不同效力和时间进程的致水肿活性。这些数据还显示了己酮可可碱对毒素A和B诱导的爪部水肿的抑制作用。此外，己酮可可碱和沙利度胺均显著抑制艰难梭菌毒素诱导的中性粒细胞迁移。
