The role of leukotriene B4 in Clostridium difficile toxin A-induced ileitis in rats.
OBJECTIVE
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.
McVey
Douglas C
DC
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.
Vigna
Steven R
SR
D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004306:Dose-Response Relationship, Immunologic; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology*; D004768:Enterotoxins / Q000378:metabolism / Q000494:pharmacology*; D007079:Ileitis / Q000276:immunology*; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism; D007975:Leukotriene B4 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels
D001427:Bacterial Toxins; D004768:Enterotoxins; D007473:Ion Channels; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C041348:tcdA protein, Clostridium difficile; D007975:Leukotriene B4