Peterson J W, Whipp S C
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston 77555-1019.
Infect Immun. 1995 Apr;63(4):1452-61. doi: 10.1128/iai.63.4.1452-1461.1995.
The mechanisms which enable cholera toxin (CT) and the Escherichia coli heat-stable enterotoxins (STa and STb) to stimulate intestinal secretion of water and electrolytes are only partially understood. CT evokes the synthesis of 3',5'-cyclic AMP (cAMP), and STa is known to elevate intestinal levels of 3',5'-cyclic GMP (cGMP). Neither of these recognized second messengers appears to mediate E. coli STb responses. We compared the secretory effects of CT, STa, and STb using the pig intestinal loop model and also measured the effects of toxin challenge on the synthesis of cAMP, cGMP, and prostaglandins (e.g., prostaglandin E2 [PGE2]), as well as on the release of 5-hydroxytryptamine (5-HT) from intestinal enterochromaffin cells. All three enterotoxins elicited fluid accumulation within a 2-h observation period. A combination of maximal doses of STa with STb yielded additive effects on fluid accumulation, which suggested different mechanisms of action for these toxins. Similarly, challenge of pig intestinal loops with a combination of CT and STb resulted in additive effects on fluid accumulation and luminal release of 5-HT. Unlike its effect on intestinal tissues from other animals, CT did not appear to elicit a dose-dependent cAMP response measurable in mucosal extracts from pig small intestine. In contrast, luminal fluid from CT-challenged pig intestinal loops contained dose-related amounts of cAMP and PGE2 that had been secreted from the mucosa. cAMP responses to STa or STb could not be demonstrated in either mucosal tissue or luminal fluid. In contrast, cGMP levels were increased in the intestinal fluid of loops challenged with STa but not in those challenged with STb. While the mechanisms of action of CT and STa are thought to involve impulse transmission via the enteric nervous system, we demonstrated significant stimulation of PGE2 synthesis and 5-HT release for CT and STb but very little for STa. We conclude from these data that the mechanisms of action of STa, STb, and CT are distinct, although the mode of action of STb may have some similarity to that of CT. Since STb stimulated the release of both PGE2 and 5-HT from the intestinal mucosa, the data suggested the potential for an effect of STb on the enteric nervous system.
霍乱毒素（CT）以及大肠杆菌热稳定肠毒素（STa和STb）刺激肠道分泌水和电解质的机制仅得到部分了解。CT可诱发3',5'-环磷酸腺苷（cAMP）的合成，已知STa可提高肠道中3',5'-环磷酸鸟苷（cGMP）的水平。这两种公认的第二信使似乎都不介导大肠杆菌STb的反应。我们使用猪肠袢模型比较了CT、STa和STb的分泌效应，还测量了毒素刺激对cAMP、cGMP和前列腺素（如前列腺素E2 [PGE2]）合成的影响，以及对肠道肠嗜铬细胞释放5-羟色胺（5-HT）的影响。在2小时的观察期内，所有三种肠毒素均引起液体蓄积。最大剂量的STa与STb联合使用对液体蓄积产生相加效应，这表明这些毒素的作用机制不同。同样，用CT和STb联合刺激猪肠袢对液体蓄积和5-HT的管腔释放产生相加效应。与对其他动物肠道组织的作用不同，CT似乎并未引起猪小肠黏膜提取物中可测量的剂量依赖性cAMP反应。相反，用CT刺激的猪肠袢的管腔液中含有与剂量相关的、从黏膜分泌的cAMP和PGE2。在黏膜组织或管腔液中均未证明对STa或STb有cAMP反应。相比之下，用STa刺激的肠袢肠液中cGMP水平升高，而用STb刺激的肠袢肠液中cGMP水平未升高。虽然认为CT和STa的作用机制涉及通过肠神经系统的冲动传递，但我们证明CT和STb可显著刺激PGE2合成和5-HT释放，而STa的刺激作用很小。我们从这些数据得出结论，STa、STb和CT的作用机制不同，尽管STb的作用方式可能与CT有一些相似之处。由于STb刺激了肠道黏膜中PGE2和5-HT的释放，这些数据表明STb可能对肠神经系统有影响。
