Treatment with BX471, a nonpeptide CCR1 antagonist, protects mice against acute pancreatitis-associated lung injury by neutrophil recruitment
Treatment with BX471, a nonpeptide CCR1 antagonist, protects mice against acute pancreatitis-associated lung injury by neutrophil recruitment
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DOI：
10.1097/mpa.0b013e31802e7598
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发表时间：
2007-03-01
期刊：
影响因子：
2.9
通讯作者：
Bhatia, Madhav
中科院分区：
文献类型：
--
作者：
He, Min;Horuk, Richard;Bhatia, Madhav
目的：趋化因子及其受体在急性胰腺炎的发病机制中起关键作用。BX471在人和小鼠中均是一种有效的非肽类CC趋化因子受体1拮抗剂。本研究的目的是评估BX471预防性和治疗性处理对小鼠实验性急性胰腺炎的影响，并探究其潜在机制。
方法：通过每小时腹腔注射雨蛙肽诱导小鼠急性胰腺炎。BX471进行预防性或治疗性给药，并评估胰腺炎症和肺损伤。通过逆转录聚合酶链反应和免疫组织化学研究细胞间黏附分子1、P -选择素和E -选择素的表达。
结果：在雨蛙肽诱导的急性胰腺炎中，BX471治疗通过减轻髓过氧化物酶活性（中性粒细胞募集的一个指标）以及组织切片中肺的形态学改变，显著保护小鼠免受与雨蛙肽诱导的胰腺炎相关的肺损伤。BX471治疗对胰腺损伤影响较小。与溶媒处理组相比，BX471阻断CC趋化因子受体1还在肺和胰腺的mRNA和蛋白质水平下调了细胞间黏附分子1、P -选择素和E -选择素的表达。
结论：这些发现表明，通过靶向CC趋化因子受体1干扰中性粒细胞迁移和活化可能是预防急性胰腺炎疾病进展的一种有前景的策略。
Objectives: Chemokines and their receptors play a key role in the pathogenesis of acute pancreatitis. BX471 is a potent nonpeptide CC chemokine receptor I 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 tran scriptase-polymerase chain reaction and immunohistochemistry.Results: In cecrulein-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 I 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 I may represent a promising strategy to prevent disease progression in acute pancreatitis.