Article

Treatment with BX471, a nonpeptide CCR1 antagonist, protects mice against acute pancreatitis-associated lung injury by modulating neutrophil recruitment.

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Bldg MD2, 18 Medical Drive, Singapore.
Pancreas (impact factor: 2.39). 04/2007; 34(2):233-41. DOI:10.1097/mpa.0b013e31802e7598 pp.233-41
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    Article: Potential Role of CC Chemokines and their Receptors in the Development of Respiratory Diseases
    Lin Tong, Yaoli Wang, Jing Bi, Dong Yang, Chunxue Bai, Xiangdong Wang
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    ABSTRACT: Increasing evidence suggests that the chemokine system coordinates leukocyte migration in immunity and in-flammation, involving in the pathogenesis of many pulmonary diseases. Chemokines are small proteins which interact with specific receptors to exert their chemotactic functions for inflammatory cells and constitutive cells. Among the com-plex system, CC chemokine receptors (CCRs) represent a subfamily of chemokine receptor, which is considered to play an important role in the pathogenesis of diseases characterized by disordered inflammation and immunity, among which some respiratory diseases, such as asthma, chronic obstructive pulmonary disease, acute lung injury, comprise one impor-tant part. The present paper reviewed the research of possible relationship and progress between this system and human lung diseases. Chemokines and their receptors are essential components of Th1-and Th2-mediated responses via the re-cruitment of lymphocytes and macrophages. The local expression of homeostatic chemokines in pulmonary also plays an important role in protective immune responses. Thus, it is important to understand the potential role of CCRs in respira-tory diseases and it may provide exciting new targets for therapeutic intervention.
    Journal of Epithelial Biology & Pharmacology 01/2008; 1:76-84.
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Keywords

acute pancreatitis
 
attenuating myeloperoxidase activity
 
Blocking CC chemokine receptor 1
 
CC chemokine receptor 1
 
cerulein-induced acute pancreatitis
 
cerulein-induced pancreatitis
 
disease progression
 
E-selectin expression
 
experimental acute pancreatitis
 
histological sections
 
hourly intraperitoneal injection
 
intercellular adhesion molecule 1
 
lung injury
 
lung morphological changes
 
neutrophil recruitment
 
potent nonpeptide CC chemokine receptor 1 antagonist
 
protein levels
 
reverse transcriptase-polymerase chain reaction
 
underlying mechanisms
 
vehicle-treated groups