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Am J Physiol Gastrointest Liver Physiol (January 18, 2007). doi:10.1152/ajpgi.00420.2006
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Submitted on September 11, 2006
Accepted on January 10, 2007

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

Min He1, Richard Horuk2, Shabbir Moochhala3, and Madhav Bhatia4*

1 Pharmacology, National University of Singapore, Singapore, Singapore, Singapore
2 Immunology, Berlex Biosciences, Richmond, California, United States
3 Combat Care and Performance Programme, DSO National Laboratories, Singapore, Singapore, Singapore
4 Department of Pharmacology, National University of Singapore, Singapore, Singapore

* To whom correspondence should be addressed. E-mail: mbhatia{at}nus.edu.sg.

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 non-peptide CCR1 (CC chemokine receptor-1) 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 CLP (cecal ligation and puncture) induced sepsis in the mouse and to investigate the underlying mechanisms. In sepsis induced by CLP, treatment with BX471 significantly protected mice against lung and liver injury by attenuating MPO (myeloperoxidase) 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 down-regulated intercellular adhesion molecule-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.




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