中文摘要：

目的研究胰岛素样生长因子-1受体（insulin-like growth factor 1 receptor,IGF-1R）的选择性抑制剂PQ401在体内外的抗炎效应。方法体外实验：小鼠RAW264.7细胞株经0.1、1、10μmol/L PQ401预作用1 h后,加入10μg/m L脂多糖（LPS）作用12 h,采用酶联免疫吸附实验（ELISA）检测细胞上清肿瘤坏死因子-α（TNF-α）、白细胞介素（IL-1β、IL-6）的含量。另将小鼠RAW264.7细胞株经10μmol/L PQ401预作用1 h后,加入10μg/m L LPS作用6、12、24 h后再次检测以上指标的变化。体内实验：将50只成年雄性C57BL/6小鼠按随机数字表法分为对照组、模型组和不同剂量PQ401组,每组10只。腹腔注射LPS 10 mg/kg制备急性炎症反应小鼠模型,对照组腹腔注射等量二甲基亚砜（DMSO）,PQ401组分别腹腔注射LPS 10 mg/kg和PQ401 25、50、100 mg/kg。于给药12 h后通过ELISA检测血清和肝组织中TNF-α、IL-1β、IL-6的含量;用全自动生化分析仪测定血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）及总胆红素（TBil）水平;采用Western blot检测肝细胞核内核转录因子-κB p65（NF-κB p65）的含量。结果与LPS单独作用组相比,PQ401呈浓度和时间依赖性降低RAW264.7细胞上清中TNF-α、IL-1β、IL-6的水平。在LPS诱导的小鼠急性腹膜炎模型中,小鼠经LPS注射12 h后表现为精神萎靡、活动减少,而PQ401组小鼠的精神状态、活动均好于模型组。PQ401治疗后能有效降低LPS所致急性腹膜炎小鼠血清中TNF-α、IL-1β、IL-6的含量,降低肝组织TNF-α、IL-1β的水平和NF-κB p65的含量。结论 PQ401在体内外对LPS诱导的炎症因子分泌具有明显的抑制效应。

英文摘要：

Objective To determine the anti-inflammatory effect of insulin-like growth factor1 receptor（ IGF-1R） selective inhibitor PQ401 in vitro and in vivo. Methods RAW264. 7 cells were preincubated with 0. 1,1 and 10 μmol/L PQ401 for 1 h and then stimulated with 10 μg/m L lipopolysaccharide（ LPS） for 12 h. After RAW264. 7 cells were treated with 10 μmol/L PQ401 for 1 h,followed by 10 μg /m L LPS stimulation for 6,12 and 24 h,the culture supernatants of the above cells were checked for the determination of tumor necrosis factor-α（ TNF-α）,interleukin 1β（ IL-1β） and interleukin 6（ IL-6） by enzyme linked immunosorbent assay（ ELISA）. Fifty C57 BL /6 mice were randomly divided into a control group,a model group and different dose PQ401 groups by 10 animals per group. Intra-peritoneal injection of10 mg/kg LPS was given to the mice to establish the acute inflammatory model. The control group was intraperitoneally injected equal dimethyl sulfoxide. The PQ401 group were differently intra-peritoneally injected10 mg/kg LPS and 25,50,100 mg/kg. All the mice were sacrificed in 12 h after injection. Blood samples were collected for the determination of TNF-α,IL-1β and IL-6 by ELISA,and for determination of alanine aminotransferase（ ALT）,aspartate aminotransferase（ AST） and total bilirubin（ TBil） with an automatic biochemistry analyzer. Hepatic homogenate was also collected for detecting the expression of nuclear factor-κB p65（ NF-κB p65） by Western blotting. Results Compared with LPS alone,PQ401 resulted significant decreases of TNF-α,IL-1β and IL-6 in a dose- and time-dependent manner in the culture supernatants. In12 h after modeling,the mice in the model group became lethargic and quiet,but PQ401 treatment was found to be able to greatly improve the general status of the mice. PQ401 could lower the serum levels of TNF-α,IL-1β and IL-6,and inhibit the liver levels of TNF-α,IL-1β and NF-κB p65. Conclusion PQ401 can inhibit the secretion of LPS-induced inflammatory cytokines i