The role of leukotriene B4 in Clostridium difficile toxin A-induced ileitis in rats.

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.

• Authors: Douglas C McVey, Steven R Vigna
• Journal: Gastroenterology (Gastroenterology) Vol. 128 Issue 5 Pg. 1306-16 (May 2005) ISSN: 0016-5085 [Print] United States
• PMID: 15887113 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bacterial Toxins
• Enterotoxins
• Ion Channels
• TRPV Cation Channels
• Trpv1 protein, rat
• tcdA protein, Clostridium difficile
• Leukotriene B4

Topics

• Animals
• Bacterial Toxins (metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Immunologic
• Enterocolitis, Pseudomembranous (immunology)
• Enterotoxins (metabolism, pharmacology)
• Ileitis (immunology)
• In Vitro Techniques
• Ion Channels (metabolism)
• Leukotriene B4 (immunology, metabolism, pharmacology)
• Male
• Rats
• Rats, Sprague-Dawley
• TRPV Cation Channels