Role of platelet activating factor in the inflammatory and secretory effects of Clostridium difficile toxin A.
Clostridium difficile is a major recognized cause of antibiotic-associated diarrhea, an effect mediated through its toxin A. Toxin A has been reported to disrupt epithelial tight junctions, attract neutrophils, and cause striking intestinal inflammation and secretion. Having demonstrated that phospholipase A2 inhibitors block the secretory effects of toxin A, we next wished to examine whether platelet activating factor (PAF) was involved in either the direct epithelial or secretory effects of toxin A. The effects of toxin A on net secretion in ligated rabbit ileal segments were significantly inhibited by the PAF antagonists 10(-4)-10(-5) M BN 52021, 10(-5) M WEB 2170, or 10(-5) M SR 27417 by 59-102%. SR 27417 also inhibited secretion induced by toxin A in loops adjacent to the drug (by 58%). Furthermore, the striking inflammation and epithelial disruption seen at 6 h and ligated ileal segments with toxin A was largely prevented by simultaneous treatment with the PAF antagonist SR 27417. In addition, we noted a significant synergistic effect of 10(-8) M PAF with 10 micrograms/ml toxin A in the ligated rabbit ileal segments. To examine direct effects of PAF antagonists on toxin A in T-84 epithelial cell monolayers, rhodamine-labeled phalloidin stained F-actin demonstrated significant disruption of F-actin by toxin A that was reduced by the PAF antagonist BN 52021 or WEB 2170. However, the PAF antagonists (10(-4) M WEB, 10(-5) M BN or 10(-4) M SR) failed to alter the disruption of T-84 cell tissue resistance by C. difficile toxin A (0.03 micrograms/ml). We conclude that PAF may be involved in the secretory effects of C. difficile toxin A, and that PAF antagonists deserve further study in C. difficile diarrhea.
Fonteles, M; Fang, G; Thielman, NM; Yotseff, PS; Guerrant, RL
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