The role of leukotriene B4 in Clostridium difficile toxin A-induced ileitis in rats |
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Authors: | McVey Douglas C Vigna Steven R |
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Affiliation: | Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA. |
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Abstract: | BACKGROUND & AIMS: Clostridium difficile toxin A is a potent intestinal inflammatory agent that has been shown to act at least partially by neurogenic mechanisms involving activation of the transient receptor potential vanilloid 1 (TRPV1) (capsaicin) receptor. We tested the hypothesis that leukotriene B4 (LTB4) mediates the effects of toxin A via activation of the TRPV1 receptor. METHODS: Isolated rat ileal segments were pretreated with pharmacologic agents before intraluminal injection of toxin A or LTB4. After 3 hours, the treated segments were removed and inflammation was assessed by luminal fluid accumulation, myeloperoxidase activity, and histology. RESULTS: LTB4 caused ileitis similar to that caused by toxin A and antagonism of TRPV1 receptors but not LTB4 receptors inhibited LTB4-induced inflammation. LTB4 also stimulated TRPV1-mediated substance P release and pretreatment with a specific substance P-receptor antagonist blocked LTB4-induced substance P action and ileitis. Inhibition of the LTB4 biosynthetic enzyme 5-lipoxygenase inhibited toxin A-induced increases in ileal LTB4 levels and toxin A- but not LTB4-induced ileitis. CONCLUSIONS: LTB4 mediates the inflammatory effects of toxin A via activation of TRPV1 receptors. |
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Keywords: | BLT, leukotriene B4 receptor 5-LO, 5-lipoxygenase I-RTX, 5′-iodoresiniferatoxin LTB4, leukotriene B4 MPO, myeloperoxidase NDGA, nordihydroguaiaretic acid NK-1R-ir, neurokinin-1 receptor immunoreactive TRPV1, transient receptor potential vanilloid 1 2-AG, 2-arachidonoyl glycerol |
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