Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation
Tyrphostin AG-490 inhibited the acute phase of zymosan-induced inflammation
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DOI：
10.1016/j.intimp.2008.06.013
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发表时间：
2008-11-01
影响因子：
5.6
通讯作者：
Ivanovska, Nina
中科院分区：
文献类型：
--
作者：
Dimitrova, Petya;Ivanovska, Nina
Tyrphostins是亚苄基丙二腈的衍生物，被认为是酪氨酸激酶抑制剂，已被应用于一些急性炎症条件模型，如LPS和酵母多糖诱导的休克。在本研究中，我们研究了酪氨酸磷酸化酶抑制剂AG-490对小鼠腹腔注射酵母聚糖（1 mg/g体重）诱导的多器官衰竭发展的影响。酵母多糖给药后24小时评估器官功能障碍和全身炎症。用AG-490（剂量，5 mg/kg i.p.同时与酵母聚糖）处理小鼠，降低腹膜中的细胞数量和NO水平。灌洗。该物质可降低肌酐（肾衰竭指标）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和胆红素（肝功能障碍指标）的升高，并防止凝血时间加速。注射酵母聚糖导致TNF-α和IL-6的血清水平显著增加，这被AG-490强烈抑制。Tyrphostin阻断了肝脏中iNOS和TNF-α R的表达。此外，免疫组织化学显示，减少磷酸化的Stat1和Stat3。总之，在酵母聚糖诱导的非感染性休克中施用酪氨酸磷酸化抑制剂AG-490显著提高了存活率，并且导致多器官衰竭的症状较少。(C)2008 Elsevier B.V.保留所有权利。
Tyrphostins, derivatives of benzylidene malononitrile are recognized as tyrosine kinase inhibitors that have been applied in some models of acute inflammatory conditions, like LPS and zymosan-induced shock. In the present study, we have investigated the effects of tyrphostin AG-490, on the development of multiple organ failure induced by i.p. injection of zymosan (1 mg/g body weight) in mice. Organ dysfunction and systemic inflammation was estimated 24 h after zymosan administration. Treatment of mice with AG-490 (dose, 5 mg/kg i.p. simultaneously with zymosan) decreased the number of cells and the level of NO in the peritoneal. lavage. The substance attenuated the elevation of creatinine (indicator of renal failure), atanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin (indicators for liver dysfunction) and prevented the accelerated coagulation time. The injection of zymosan resulted in a substantial increase in the serum level of TNF-alpha and IL-6, which was strongly inhibited by AG-490. Tyrphostin abolished the expression of iNOS and TNF-alpha R in the liver. Moreover, immunohistochemistry of liver showed decreased phosphorylation of Stat1 and Stat3. In conclusion, the administration of tyrphostin AG-490 in zymosan-induced nonseptic shock significantly improved the rate of survival and lead to less exerted signs of multiple organ failure. (C) 2008 Elsevier B.V. All rights reserved.