Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0207118 on July 26, 2007

Published online before print July 26, 2007
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(Journal of Leukocyte Biology. 2007;82:1239-1246.)
© 2007 by Society for Leukocyte Biology

Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice

Pasquale Buanne*, Emma Di Carlo{dagger},{ddagger}, Lorenzo Caputi*, Laura Brandolini*, Marco Mosca*, Franca Cattani*, Luigi Pellegrini*, Leda Biordi§, Gino Coletti, Carlo Sorrentino{dagger},{ddagger}, Guido Fedele||, Francesco Colotta*,#, Gabriella Melillo* and Riccardo Bertini*,1

* Department of Preclinical Pharmacology, Dompé pha.r.ma s.p.a., L’Aquila, Italy;
{dagger} Department of Oncology and Neurosciences, Surgical Pathology Section, "G. d'Annunzio" University, Chieti, Italy;
{ddagger} Ce. S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy;
§ Experimental Medicine Department, University of L’Aquila, L’Aquila, Italy;
Operative Unit of Pathological Anatomy, S. Salvatore Regional Hospital, L’Aquila, Italy;
|| Biometry Unit, Dompé pha.r.ma s.p.a., Milan, Italy; and
# Nerviano Medical Sciences, Milan, Italy

1 Correspondence: Department of Preclinical Pharmacology, Dompé pha.r.ma s.p.a., Via Campo di Pile 67100 L’Aquila, Italy. E-mail: bertini{at}dompe.it

Polymorphonuclear leukocyte infiltration and activation into colonic mucosa are believed to play a pivotal role in mediating tissue damage in human ulcerative colitis (UC). Ligands of human CXC chemokine receptor 1 and 2 (CXCR1/R2) are chemoattractants of PMN, and high levels were found in the mucosa of UC patients. To investigate the pathophysiological role played by CXCR2 in experimental UC, we induced chronic experimental colitis in WT and CXCR2–/– mice by two consecutive cycles of 4% dextran sulfate sodium administration in drinking water. In wild-type (WT) mice, the chronic relapsing of DSS-induced colitis was characterized by clinical signs and histopathological findings that closely resemble human disease. CXCR2–/– mice failed to show PMN infiltration into the mucosa and, consistently with a key role of PMN in mediating tissue damage in UC, showed limited signs of mucosal damage and reduced clinical symptoms. Our data demonstrate that CXCR2 plays a key pathophysiological role in experimental UC, suggesting that CXCR2 activation may represent a relevant pharmacological target for the design of novel pharmacological treatments in human UC.

Key Words: rodent • neutrophils • inflammation




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