Role of inducible cyclooxygenase and prostaglandins in Clostridium difficile toxin A-induced secretion and inflammation in an animal model.
Cyclooxygenase (Cox)-2 expression and inhibition were investigated in a rabbit ileal loop model of Clostridium difficile colitis and diarrhea. Intestinal tissue stimulated with C. difficile toxin A showed up-regulation of Cox-2 expression in lamina propria macrophages and elevated prostaglandin levels. Toxin A-stimulated loops exhibited severe inflammation and increased secretory volume. Celecoxib, a specific Cox-2 inhibitor, significantly reduced toxin A-induced prostaglandin production. Furthermore, celecoxib (> or =0.02 mg/mL) blocked both histologic damage (mean histologic grade, 1.25 vs. 3.44 in rabbits receiving toxin A alone; P<.0005) and secretion (volume:length ratio, 0.18 vs. 0.72 in those receiving toxin A alone; P=.002) in toxin A-stimulated loops in a dose-related manner. Thus, toxin A induced expression of Cox-2 in the host, and prostaglandins produced through Cox-2 were involved in the mediation of the increased secretion of electrolytes and water and the inflammatory response induced by toxin A.
Alcantara
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Division of Geographic Medicine, Department of Medicine, University of Virginia, Charlottesville,Virginia 22908, USA.
Stenson
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Steiner
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TS
Guerrant
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D000818:Animals; D001427:Bacterial Toxins / Q000633:toxicity*; D016360:Clostridioides difficile / Q000378:metabolism* / Q000472:pathogenicity; D003092:Colitis / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051546:Cyclooxygenase 2; D003967:Diarrhea / Q000382:microbiology; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000633:toxicity*; D004789:Enzyme Activation; D006801:Humans; D007082:Ileum / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011817:Rabbits
D001427:Bacterial Toxins; D004768:Enterotoxins; D007527:Isoenzymes; D008565:Membrane Proteins; C041348:tcdA protein, Clostridium difficile; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone