BLOCKAGE OF CCR1 BY NON-PEPTIDE ANTAGONIST BX471 SHOWS PROTECTIVE EFFECT AGAINST ACUTE PANCREATITIS-ASSOCIATED LUNG INJURY

Abstract

Introduction: Many studies evaluating the role of chemokines in acute pancreatitis have focused on CXC chemokines. However, more and more evidence begins to reveal that CC chemokines also play an active role in the progress of acute pancreatitis. BX471 is a potent non-peptide CCR1 (CC chemokine receptor-1) antagonist in both mouse and human. The aim of the present study is to evaluate the effect of prophylactic and therapeutic treatment with BX471 on experimental acute pancreatitis in the mouse and to investigate the underlying interaction between chemokines and adhesion molecules. Methods: Acute pancreatitis was induced in mice by hourly intraperitoneal injection of caerulein for 10 hours. BX471 was administered either 30 min before or 1 h after the first caerulein injection. Pancreatic inflammation and lung injury were assessed. The expression of ICAM-1, P-selectin and E-selectin was studied by RT-PCR and Immunohistochemistry. Results: In caerulein-induced acute pancreatitis, treatment with BX471 significantly protected mice against lung injury associated with caerulein induced pancreatitis by attenuating MPO (myeloperoxidase) activity, an indicator of neutrophil recruitment, in lungs and attenuating lung morphological changes in histological sections. Treatment with BX471 had little effect on pancreatic damage judging by plasma amylase, water content and histology examination, although pancreatic MPO activity was reduced in BX471 treated groups. Blockage CCR1 by BX471 also down-regulated ICAM-1, P-selectin and E-selectin expression at both mRNA and protein levels in lungs and pancreas compared with vehicle treated groups. Conclusions: These findings suggest that interfering with neutrophil migration and activation by blockage of CCR1 may represent a promising strategy to prevent disease progression in acute pancreatitis-associated lung injury.