Efficacy of an inhibitor of adhesion molecule expression (GI270384X) in the treatment of experimental colitis.
Modulation of adhesion molecule expression or function is regarded as a promising therapy for inflammatory conditions. This study evaluates the effects of an inhibitor of adhesion molecule expression (GI270384X) in two experimental models of colitis. Colitis of different severity was induced in C57BL/6J mice by administering 1, 2, or 3% dextran sulfate sodium (DSS). GI270384X (3, 10, or 25 mg.kg(-1).day(-1)) was administered as pretreatment or started 3 days after colitis induction. In IL-10-deficient mice, the highest dose was given for 2 wk. The clinical course of colitis, pathological changes, serum inflammatory biomarkers, expression of adhesion molecules, and leukocyte-endothelial cell interactions in colonic venules were measured in mice treated with vehicle or with active drug. In the most severe forms of colitis (2% and 3% DSS and IL-10-deficient mice), the magnitude of colonic inflammation was not modified by treatment with GI270384X. In a less severe form of colitis (1% DSS), GI270384X treatment dose dependently ameliorated the clinical signs of colitis, colonic pathological changes, and serum levels of biomarkers (IL-6 and serum amyloid A). Administration of 25 mg.kg(-1).day(-1) GI270384X abrogated upregulation of ICAM-1 in the inflamed colon but had no effect on VCAM-1 or E-selectin expression. This was associated with a significant reduction in number of rolling and firmly adherent leukocytes in colonic venules. These results indicate that GI270384X is effective in the treatment of experimental colitis of moderate severity. Reduced adhesion molecule expression and leukocyte recruitment to the inflamed intestine contribute to this beneficial effect.
Panés
Julián
J
Dept. of Gastroenterology, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain. panes@ub.edu
Aceituno
Montserrat
M
Gil
Fèlix
F
Miquel
Rosa
R
Piqué
Josep M
JM
Salas
Azucena
A
McLean
Peter
P
D000818:Animals; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D016264:Dextran Sulfate; D004305:Dose-Response Relationship, Drug; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D016753:Interleukin-10 / Q000172:deficiency; D007962:Leukocytes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D015815:Cell Adhesion Molecules; C524446:GI270384X; D011687:Purines; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D011092:Polyethylene Glycols; D016264:Dextran Sulfate