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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/G739    most recent 00059.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Panés, J. Articles by McLean, P. Search for Related Content PubMed PubMed Citation Articles by Panés, J. Articles by McLean, P.

INFLAMMATION/IMMUNITY/MEDIATORS

Efficacy of an inhibitor of adhesion molecule expression (GI270384X) in the treatment of experimental colitis

Departments of ¹Gastroenterology and ²Pathology, Hospital Clínic Barcelona, CIBER-EHD, and ³Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain; and ⁴Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline R&D Ltd., Harlow, United Kingdom

Submitted 1 February 2007 ; accepted in final form 25 July 2007

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.

endothelium; ICAM-1; leukocyte