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This Article Full Text Full Text (PDF) All Versions of this Article: 292/4/G1173    most recent 00420.2006v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by He, M. Articles by Bhatia, M. Search for Related Content PubMed PubMed Citation Articles by He, M. Articles by Bhatia, M.

INFLAMMATION/IMMUNITY/MEDIATORS

Treatment with BX471, a CC chemokine receptor 1 antagonist, attenuates systemic inflammatory response during sepsis

¹Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; ²Department of Immunology, Berlex Biosciences, Richmond, California; and ³Defense Science Organization National Laboratories, Singapore

Submitted 11 September 2006 ; accepted in final form 10 January 2007

Sepsis is a complex clinical syndrome resulting from a harmful host inflammatory response to infection. Chemokines and their receptors play a key role in the pathogenesis of sepsis. BX471 is a potent nonpeptide CC chemokine receptor-1 (CCR1) antagonist in both human and mouse. The aim of the present study was to evaluate the effect of prophylactic and therapeutic treatment with BX471 on cecal ligation and puncture-induced sepsis in the mouse and to investigate the underlying mechanisms. In sepsis induced by cecal ligation and puncture, treatment with BX471 significantly protected mice against lung and liver injury by attenuating MPO activity, an indicator of neutrophil recruitment in lungs and livers and attenuating lung and liver morphological changes in histological sections. Blocking CCR1 by BX471 also downregulated ICAM-1, P-selectin, and E-selectin expression at mRNA and protein levels in lungs and livers compared with placebo-treated groups. These findings suggest that blockage of CCR1 by specific antagonist may represent a promising strategy to prevent disease progression in sepsis.

acute respiratory distress syndrome; multiple organ dysfunction syndrome; systemic inflammatory response syndrome

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