Pyrrolidine dithiocarbamate prevents I-κB degradation and reduces microvascular injury induced by lipopolysaccharide in multiple organs

作     者：Liu, SF Ye, XB Malik, AB 

作者机构：Univ Illinois Coll Med Dept Pharmacol Chicago IL 60612 USA 

出 版 物：《MOLECULAR PHARMACOLOGY》 (分子药理学)

年 卷 期：1999年第55卷第4期

页      面：658-667页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 10[医学] 

基　　金：NHLBI NIH HHS [HL46350] Funding Source: Medline 

主　　题：抗氧化剂/治疗应用 毛细血管/病理学 毛细血管通透性/药物作用 趋化因子 CXC 趋化因子类/生物合成 趋化因子类/遗传学 DNA结合蛋白质类/代谢 酶抑制 生长物质/生物合成 生长物质/遗传学 I-κB蛋白质类 胞间黏附分子1/生物合成 胞间黏附分子1/遗传学 胞间信号肽类和蛋白质类 脂多糖类/毒性 NF-κB/代谢 中性白细胞/药物作用 中性白细胞/代谢 过氧化物酶/代谢 吡咯烷类/治疗应用 RNA 信使/生物合成 RNA 信使/药物作用 大鼠 Sprague-Dawley 休克 脓毒性/病理学 硫代氨基甲酸酯类/治疗应用 动物 男(雄)性 大鼠 

摘      要：Lipopolysaccharide (LPS) is a key mediator of multiple organ injury observed in septic shock. The mechanisms responsible for LPS-induced multiple organ injury remain obscure. In the present study, we tested the hypothesis that the LPS-induced injury occurs through activation of the transcription factor, nuclear factor-kappa B (NF-kappa B). We examined the effects of inhibiting NF-kappa B activation in vivo in the rat on LPS-induced: 1) gene and protein expression of the cytokine-inducible neutrophil chemoattractant (CINC) and intercellular adhesion molecule-1 (ICAM-1);b) neutrophil influx into lungs, heart, and liver;and c) increase in microvascular permeability induced by LPS in these organs. LPS (8 mg/kg, i.v.) challenge of rats activated NF-kappa B and induced CINC and ICAM-1 mRNA and protein expression. Pretreatment of rats with pyrrolidine dithiocarbamate (50, 100, and 200 mg/kg, i.p.), an inhibitor of NF-kappa B activation, prevented LPS-induced I-kappa B alpha degradation and the resultant NF-kappa B activation and inhibited, in a dose-related manner, the LPS-induced CINC and ICAM-1 mRNA and protein expression. Pyrrolidine dithiocarbamate also markedly reduced the LPS-induced tissue myeloperoxidase activity (an indicator of tissue neutrophil retention) and the LPS-induced increase in microvascular permeability in these organs. These results demonstrate that NF-kappa B activation is an important in vivo mechanism mediating LPS-induced CINC and ICAM-1 expression, as well as neutrophil recruitment, and the subsequent organ injury. Thus, inhibition of NF-kappa B activation may be an important strategy for the treatment of sepsis-induced multiple organ injury.