Treatment with BX471, a nonpeptide CCR1 antagonist, protects mice against acute pancreatitis-associated lung injury by modulating neutrophil recruitment.
OBJECTIVE
Chemokines and their receptors play a key role in the pathogenesis of acute pancreatitis. BX471 is a potent nonpeptide 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 experimental acute pancreatitis in the mouse and to investigate the underlying mechanisms.


METHODS
Acute pancreatitis was induced in mice by hourly intraperitoneal injection of cerulein. BX471 was administered either prophylactically or therapeutically, and pancreatic inflammation and lung injury were assessed. The expression of intercellular adhesion molecule 1, P-selectin, and E-selectin was studied by reverse transcriptase-polymerase chain reaction and immunohistochemistry.


RESULTS
In cerulein-induced acute pancreatitis, treatment with BX471 significantly protected mice against lung injury associated with cerulein-induced pancreatitis by attenuating myeloperoxidase activity, an indicator of neutrophil recruitment, and lung morphological changes in histological sections. Treatment with BX471 had little effect on pancreatic damage. Blocking CC chemokine receptor 1 by BX471 also down-regulated intercellular adhesion molecule 1, P-selectin, and E-selectin expression at mRNA and protein levels in both lungs and pancreas compared with vehicle-treated groups.


CONCLUSIONS
These findings suggest that interfering with neutrophil migration and activation by targeting CC chemokine receptor 1 may represent a promising strategy to prevent disease progression in acute pancreatitis.
He
Min
M
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Bldg MD2, 18 Medical Drive, Singapore.
Horuk
Richard
R
Bhatia
Madhav
M
D000208:Acute Disease; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D004195:Disease Models, Animal; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000187:drug effects*; D019007:P-Selectin / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000276:immunology / Q000473:pathology; D010195:Pancreatitis / Q000150:complications* / Q000276:immunology / Q000473:pathology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000276:immunology; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control
C515300:CCR1 protein, human; C515301:Ccr1 protein, mouse; D054407:Chemokine CCL4; D018946:Chemokine CCL5; 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; C411885:BX 471