Ketotifen inhibits Clostridium difficile toxin A-induced enteritis in rat ileum.
BACKGROUND
Clostridium difficile toxin A is the principal mediator of inflammatory enterocolitis in experimental animals. The purpose of this study was to explore the effect of ketotifen, an anti-inflammatory drug, on toxin A-induced enterotoxicity in rat ileum.


METHODS
The effects of intragastric administration of ketotifen on secretion, mannitol permeability, histological damage, and mucosal levels of leukotriene B4, leukotriene C4, and platelet activating factor in toxin A-exposed rat ileal loops were measured in vivo. The effects of ketotifen on toxin A-mediated release of rat mast cell protease II (rat mucosa mast cell product) release were also measured in rat ileal explants in vitro. The effect of ketotifen on neutrophil migration in vitro was also evaluated.


RESULTS
Ketotifen pretreatment inhibited toxin A-associated intestinal secretion by 42.5% and mannitol permeability by 56.3% and reduced epithelial cell inflammation and necrosis. These effects were associated with reduced levels of leukotriene B4 by 65.8%, leukotriene C4 by 88.8%, platelet activating factor by 77.8%, and inhibition of rat mast cell protease II by 58.4%. In addition, pretreatment of neutrophils with ketotifen inhibited neutrophil migration in vitro.


CONCLUSIONS
The protective effect of ketotifen in this animal model was associated with significant inhibition of release of mast cells and neutrophil derived mediators, supporting their involvement in C. difficile enteritis.
Section of Gastroenterology, University Hospital, Boston University School of Medicine, Massachusetts.
C
C
Pothoulakis
F
F
Karmeli
C P
CP
Kelly
R
R
Eliakim
M A
MA
Joshi
C J
CJ
O'Keane
I
I
Castagliuolo
J T
JT
LaMont
D
D
Rachmilewitz
D000818:Animals; D001427:Bacterial Toxins; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D010450:Endopeptidases / Q000032:analysis / Q000378:metabolism; D004751:Enteritis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004768:Enterotoxins / Q000494:pharmacology*; D007077:Ileal Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007082:Ileum / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000737:chemistry; D007665:Ketotifen / Q000494:pharmacology*; D007975:Leukotriene B4 / Q000032:analysis; D008297:Male; D008353:Mannitol / Q000493:pharmacokinetics; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D010539:Permeability; D010972:Platelet Activating Factor / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013189:SRS-A / Q000032:analysis
D001427:Bacterial Toxins; D004768:Enterotoxins; D010972:Platelet Activating Factor; D013189:SRS-A; C041348:tcdA protein, Clostridium difficile; D007975:Leukotriene B4; D008353:Mannitol; D010450:Endopeptidases; D007665:Ketotifen