Bosentan, an endothelin receptor antagonist, reduces leucocyte adhesion and inflammation in a murine model of inflammatory bowel disease.
OBJECTIVE
Endothelins, a group of polyfunctional cytokines, induce the adhesion of circulating leucocytes to venous endothelium, an initial step in the pathogenesis of a cellular infiltrate in inflammatory bowel disease (IBD). The effect of bosentan, a non-selective endothelin receptor antagonist, on leucocyte adhesion and inflammation in a murine model of IBD was studied.


METHODS
Thirty BALB/c mice were divided into three groups of 10 animals: untreated controls, chronic colitis [dextran sodium sulphate (DSS), 3% w/v for 30 days], and treatment with bosentan (30 mg/kg i.p. daily on days 26-30). On day 30, adherent and rolling leucocytes and the average rolling velocity were assessed by intravital microscopy. Clinical and histological activity of inflammation were assessed by the disease activity index and modified Dieleman score, respectively.


METHODS
Kruskal-Wallis test was used, followed by Dunn's method. A value of p<0.05 was considered significant.


RESULTS
Compared to healthy controls, mice treated with DSS showed pronounced clinical and histological inflammation, and a higher number of rolling and adhering leucocytes in colonic submucosal venules. Therapy with bosentan significantly reduced clinical and histological inflammation. Adherent leucocyte levels were markedly lower (1.2+/-0.3 vs 23.7+/-2.8 adherent cells per 0.01 mm2, p<0.05). The number of rolling leucocytes was lower but not significantly different. However, rolling velocity was significantly higher (91.5+/-14.0 vs 19.0+/-1.6 microm/s, p<0.05).


CONCLUSIONS
Bosentan reduces the adhesion of leucocytes in colonic submucosal venules and reduces inflammation in this mouse model of IBD. By inhibiting leucocyte adhesion, a crucial step in the recruitment of leucocytes to the inflamed tissue, bosentan is a potent therapeutic drug in this animal model. Further studies are necessary to investigate the role of bosentan as a novel drug in human IBD.
Anthoni
Christoph
C
Department of General Surgery, Westfalian Wilhelm's University, Muenster, Germany. canth1@1suhsc.edu
Mennigen
Rudolf B
RB
Rijcken
Emile J M
EJ
Laukötter
Mike G
MG
Spiegel
Hans-Ullrich
HU
Senninger
Norbert
N
Schürmann
Guido
G
Krieglstein
Christian F
CF
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000077300:Bosentan; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000473:pathology*; D007962:Leukocytes / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan