Treatment with BX471, a nonpeptide CCR1 antagonist, protects mice against acute pancreatitis-associated lung injury by modulating neutrophil recruitment.
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.
Article: Potential Role of CC Chemokines and their Receptors in the Development of Respiratory Diseases[show abstract] [hide abstract]
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.