Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0408231 on July 24, 2008

Published online before print July 24, 2008
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(Journal of Leukocyte Biology. 2008;84:1213-1221.)
© 2008 by Society for Leukocyte Biology

The selective nonpeptide CXCR2 antagonist SB225002 ameliorates acute experimental colitis in mice

Allisson Freire Bento*, Daniela Ferraz Pereira Leite*, Rafaela Franco Claudino*, Daniela Balz Hara*, Paulo César Leal{dagger} and João B. Calixto*,1

* Departamento de Farmacologia, Centro de Ciências Biológicas, and
{dagger} Departamento de Química, Centro de Ciências Físicas e Matemáticas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

1 Correspondence: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Campus Universitário, Trindade, Bloco D, CCB, Caixa Postal 476, CEP 88049-900, Florianópolis, SC, Brazil. E-mail: calixto{at}farmaco.ufsc.br or calixto3{at}terra.com.br

ABSTRACT

Although neutrophils are strongly implicated in eliminating pathogens, excessive recruitment may cause tissue damage. Therefore, reducing cell influx during an inflammatory process may be a potential target for treating inflammatory bowel diseases (IBD). As CXCR2 is involved in neutrophil migration, this study aimed to evaluate whether the systemic therapeutic treatment with selective CXCR2 antagonist SB225002 ameliorates experimental colitis, which was induced in mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). After colitis establishment (24 h), mice were treated with SB225002. At later time-points, up to 72 h, mice were monitored for body weight loss and overall mortality. At the time of sacrifice, colonic tissues were scored for macro- and microscopic damage, and cytokine levels, myeloperoxidase (MPO) activity, and protein expression were analyzed. TNBS administration induced macro- and microscopic damage in colon tissue, leading in most cases to animal death. Curative treatment with SB225002 significantly reduced all of the parameters analyzed, leading to an improvement of inflammatory signs. SB225002 reduced neutrophil influx, MPO activity, IL-1β, MIP-2, and keratinocyte-derived chemokine (KC) levels and the expression of vascular endothelial growth factor, inducible NO synthase, and cyclooxygenase-2 proteins into the colon tissue. Levels of IL-4 and IL-10 were increased significantly in the colons of animals treated with SB225002. Additionally, curative treatment with mouse anti-KC significantly reduced MPO activity and colonic damage. These results taken together demonstrate that a selective blockade of CXCR2 consistently reduced TNBS-induced colitis, suggesting that the use of SB225002 is a potential therapeutic approach for the treatment of IBD and other related inflammatory disorders.

Key Words: chemokines • neutrophil migration • trinitrobenzene sulfonic acid-induced colitis • mouse






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