Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis
Treatment with bindarit, a blocker of MCP-1 synthesis, protects mice against acute pancreatitis
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DOI：
10.1152/ajpgi.00435.2004
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发表时间：
2005-06-01
影响因子：
4.5
通讯作者：
Guglielmotti, A
中科院分区：
文献类型：
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作者：
Bhatia, M;Ramnath, RD;Guglielmotti, A
趋化因子被认为在急性胰腺炎的发病机制中起关键作用。我们先前已经表明胰腺腺泡细胞产生趋化因子单核细胞趋化蛋白（MCP）-1对雨蛙素过度刺激的反应，表明腺泡衍生的MCP-1是急性胰腺炎炎症的早期介质。阻断趋化因子的产生或作用是多种炎性疾病（如急性胰腺炎）中药物干预的主要靶点。2-甲基-2-[[1-（苯甲基）-1H-吲唑-3基]甲氧基]丙酸（bindarit）已显示在体外和体内优先抑制单核细胞中MCP-1的产生，而不影响细胞因子IL-1、IL-6或趋化因子IL-8、蛋白巨噬细胞炎性-1 α和RANTES的产生。本研究的目的是确定MCP-1在急性胰腺炎中的作用。在雨蛙肽过度刺激诱导的急性胰腺炎模型中，用bindarit进行预防性和治疗性治疗可显著降低胰腺中MCP-1的水平。此外，该处理显著保护小鼠免受急性胰腺炎，如胰腺中的高淀粉酶血症中性粒细胞隔离（胰腺MPO活性）减弱和胰腺切片的组织学检查中的胰腺腺泡细胞损伤/坏死所证明的。
Chemokines are believed to play a key role in the pathogenesis of acute pancreatitis. We have earlier shown that pancreatic acinar cells produce the chemokine monocyte chemotactic protein (MCP)-1 in response to caerulein hyperstimulation, demonstrating that acinar-derived MCP-1 is an early mediator of inflammation in acute pancreatitis. Blocking chemokine production or action is a major target for pharmacological intervention in a variety of inflammatory diseases, such as acute pancreatitis. 2-Methyl-2-[[1-( phenylmethyl)-1H-indazol-3yl]methoxy] propanoic acid (bindarit) has been shown to preferentially inhibit MCP-1 production in vitro in monocytes and in vivo without affecting the production of the cytokines IL-1, IL-6, or the chemokines IL-8, protein macrophage inflammatory-1 alpha, and RANTES. The present study aimed to define the role of MCP-1 in acute pancreatitis with the use of bindarit. In a model of acute pancreatitis induced by caerulein hyperstimulation, prophylactic as well as therapeutic treatment with bindarit significantly reduced MCP-1 levels in the pancreas. Also, this treatment significantly protected mice against acute pancreatitis as evident by attenuated hyperamylasemia neutrophil sequestration in the pancreas (pancreatic MPO activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections.