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VIP attenuation of the severity of experimental pancreatitis is due to VPAC1 receptor mediated inhibition of cytokine production

VIP 减轻实验性胰腺炎的严重程度是由于 VPAC1 受体介导的细胞因子产生抑制

基本信息

批准号：
14570477
负责人：
ITO Tetsuhide
金额：
$ 2.05万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Background & Aims : VIP receptor has been clarified to exist on immune cells, indicating it is possible involvement in immunity and inflammatory response. Therefore, we investigated the effects of VIP and selective agonists for two subtypes of VIP receptor (VPAC1-R and VPAC2-R agonist) on acute pancreatitis. Methods : Acute pancreatitis was induced in mice by four intraperitoneal injections of Caerulein and an injection of LPS. VIP,VPAC1-R agonist, VPAC2-R agonist or secretin (5nmol/body) was administered 30 minutes before and after the administration of LPS. Serum amylase and cytokine levels were determined and histological changes were evaluated. In vitro, IL-6 and TNF-a production by monocytes from the spleen was determined under the stimulation of LPS with VIP,VPAC1-R agonist or VPAC2-R agonist, and the expression of VPAC1-R and VPAC2-R mRNA in monocytes was examined. Results : VPAC1-R agonist significantly decreased serum amylase, IL-6 and TNF-a whereas VPAC2-R agonist markedly increased serum amylase. Histologically, VIP and VPAC1-R agonist attenuated pancreatitis although VPAC2-R agonist or secretin showed no significant effect. In vitro, VPAC1-R and VPAC2-R mRNA were obviously expressed in monocytes. Under the stimulation with LPS,VIP presented a biphasic pattern that once decreased IL-6 production from monocytes, and then enhanced at high concentration. VPAC1-R agonist reduced IL-6 levels, whereas VPAC2-R agonist increased IL-6 dose-dependently. VPAC1-R agonist reduced TNF-a levels in a dose dependent manner. Conclusions : VIP attenuated the experimental acute pancreatitis enzymatically and morphologically by inhibiting pro-inflammatory cytokine production from monocytes mainly through the VPAC1-R.

背景和目标：VIP受体已被证实存在于免疫细胞上，提示其可能参与免疫和炎症反应。因此，我们研究了VIP和VIP受体两种亚型的选择性激动剂（VPAC 1-R和VPAC 2-R激动剂）对急性胰腺炎的影响。方法：采用四次腹腔注射雨蛙肽和一次腹腔注射脂多糖的方法建立小鼠急性胰腺炎模型。VIP、VPAC 1-R激动剂、VPAC 2-R激动剂或促胰液素（5 nmol/只）分别于注射LPS前和注射LPS后30分钟注射。测定血清淀粉酶和细胞因子水平，并评价组织学变化。在体外条件下，用VIP、VPAC 1-R激动剂和VPAC 2-R激动剂刺激脾单核细胞，检测单核细胞产生IL-6和TNF-α的能力，并检测单核细胞VPAC 1-R和VPAC 2-R mRNA的表达。结果：VPAC 1-R激动剂可显著降低血清淀粉酶、IL-6和TNF-α水平，而VPAC 2-R激动剂可显著升高血清淀粉酶水平。组织学上，VIP和VPAC 1-R激动剂减轻了胰腺炎，而VPAC 2-R激动剂或促胰液素则没有明显作用。体外培养的单核细胞表达VPAC 1-R和VPAC 2-R mRNA。在LPS刺激下，VIP呈双相模式，先降低单核细胞产生IL-6，然后在高浓度时增强。VPAC 1-R激动剂降低IL-6水平，而VPAC 2-R激动剂剂量依赖性地增加IL-6水平。VPAC 1-R激动剂以剂量依赖性方式降低TNF-α水平。结论：VIP主要通过VPAC 1-R抑制单核细胞产生促炎性细胞因子，从酶和形态学上减轻实验性急性胰腺炎。