Treatment with BX471, a CC chemokine receptor 1 antagonist, attenuates systemic inflammatory response during sepsis.
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.
He
Min
M
Department of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Singapore.
Horuk
Richard
R
Moochhala
Shabbir M
SM
Bhatia
Madhav
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001065:Appendix / Q000601:surgery; D054407:Chemokine CCL4; D004195:Disease Models, Animal; D018450:Disease Progression; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects*; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018805:Sepsis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D013997:Time Factors
D000893:Anti-Inflammatory Agents; C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D054407:Chemokine CCL4; D019040:E-Selectin; D019402:Macrophage Inflammatory Proteins; D019007:P-Selectin; D010671:Phenylurea Compounds; D010880:Piperidines; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; C411885:BX 471