Effects of tyrphostins and genistein on the circulatory failure and organ dysfunction caused by endotoxin in the rat: A possible role for protein tyrosine kinase
Effects of tyrphostins and genistein on the circulatory failure and organ dysfunction caused by endotoxin in the rat: A possible role for protein tyrosine kinase
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DOI：
10.1038/sj.bjp.0701345
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发表时间：
1997-09-01
影响因子：
7.3
通讯作者：
Thiemermann, C
中科院分区：
文献类型：
--
作者：
Ruetten, H;Thiemermann, C
1 在此，我们比较了不同蛋白酪氨酸激酶活性抑制剂对 (i) 培养的巨噬细胞中内毒素（脂多糖，LPS）引起的诱导型一氧化氮 (NO) 合酶 (iNOS) 活性表达的影响，(ii) 大鼠体内 iNOS 和环加氧酶 2 (COX-2) 蛋白的诱导及活性的影响 (iii) LPS 在麻醉大鼠中引起的循环衰竭和器官功能障碍。2 用 LPS (1 μ g ml(-1)) 激活小鼠培养的巨噬细胞，在 24 小时内导致细胞上清液中亚硝酸盐（NO 形成的指标）显着增加。亚硝酸盐的增加被酪氨酸磷酸酶 AG126、AG556、AG490 或 AG1641 或金雀异黄素以剂量依赖性方式减弱（IC50：类似于 15 μM）。相比之下，酪氨酸磷酸酶Al（酪氨酸磷酸酶AC126的类似物）或大豆黄酮（染料木黄酮的类似物）对LPS引起的亚硝酸盐升高没有影响。 3给予LPS（大肠杆菌，10 mg kg（-1），静脉注射）引起低血压，并减少去甲肾上腺素（NA，1 mu g kg（-1）， 静脉注射）。用酪氨酸磷酸抑制剂 AG126、AG490、AG556、AG1641 或 A1 预处理大鼠可减轻 LPS 引起的循环衰竭。尽管金雀异黄素可减弱血管对NA的低反应性，但它并不影响LPS引起的低血压。黄豆苷元对 LPS 引起的循环衰竭没有影响。4 内毒素血症 360 分钟导致血清中 (i) 尿素和肌酐（肾衰竭指标）、(ii) 丙氨酸转氨酶 (ALT)、天冬氨酸转氨酶 (AST)、胆红素和 γ-谷氨酰转移酶 (gamma GT)（肾衰竭指标）的血清水平升高。 肝损伤/功能障碍）、脂肪酶（胰腺损伤的指标）以及乳酸（组织缺氧的指标）。所测试的酪氨酸激酶抑制剂均未对血清尿素水平升高产生显着影响，但酪氨酸磷酸酶 AG126、AG556 或 Al 显着减弱 LPS 引起的血清肌酐水平升高。此外，所有酪氨酸磷酸酶和金雀异黄酮均可减轻LPS引起的肝损伤/衰竭、胰腺损伤、低血糖和乳酸性酸中毒。相反，黄豆苷元并不能减少由 LPS 引起的器官损伤/功能障碍或乳酸性酸中毒。 5 注射 LPS 导致（90 分钟内）肿瘤坏死因子 α (TNF α) 血清水平显着升高，用任何酪氨酸磷酸酶预处理 LPS 大鼠可减弱这种升高。金雀异黄素（但不是大豆黄酮）也可以降低由 LPS 引起的血清 TNF α 水平的升高。内毒素血症 6 小时还导致肺中 iNOS 和 COX-2 蛋白的表达和活性显着增加，通过用酪氨酸磷酸酶 AG126、AG556 或染料木黄酮（而非大豆苷元）预处理 LPS 大鼠，可以减弱这种增加。 6 因此，酪氨酸磷酸酶（AG126、AG490、AG556、AG1641 或 Al）和染料木黄酮，但不能减弱这种影响。不 大豆苷元（金雀异黄素的无活性类似物），可预防 (i) 循环衰竭，(ii) 多器官功能障碍（肝和胰腺功能障碍/损伤、乳酸中毒、低血糖），以及 (iii) 诱导内毒素性休克大鼠中 iNOS 和 COX-2 蛋白及其活性。
1 Here we compared the effects of various inhibitors of the activity of protein tyrosine kinase on (i) the expression of the activity of the inducible isoform of nitric oxide (NO) synthase (iNOS) caused by endotoxin (lipopolysaccharide, LPS) in cultured macrophages, (ii) the induction of iNOS and cyclo-oxygenase 2 (COX-2) protein and activity in rats with endotoxaemia, and (iii) the circulatory failure and organ dysfunction caused by LPS in the anaesthetized rat.2 Activation of murine cultured macrophages with LPS (1 mu g ml(-1)) resulted, within 24 h, in a significant increase in nitrite (an indicator of the formation of NO) in the cell supernatant. This increase in nitrite was attenuated by the tyrphostins AG126, AG556, AG490 or AG1641 or by genistein in a dose-dependent fashion (IC50:similar to 15 mu M). In contrast, tyrphostin Al (an analogue of tyrphostin AC126) or daidzein (an analogue of genistein) had no effect on the rise in nitrite caused by LPS.3 Administration of LPS (E. coli, 10 mg kg(-1), i.v.) caused hypotension and a reduction of the presser responses elicited by noradrenaline (NA, 1 mu g kg(-1), i.v.). Pretreatment of rats with the tyrphostins AG126, AG490, AG556, AG1641 or Al attenuated the circulatory failure caused by LPS. Although genistein attenuated the vascular hyporeactivity to NA, it did not affect the hypotension caused by LPS. Daidzein did not affect the circulatory failure caused by LPS.4 Endotoxaemia for 360 min resulted in rises in the serum levels of (i) urea and creatinine (indicators of renal failure), (ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and gamma-glutamyl transferase (gamma GT) (indicators of liver injury/dysfunction), lipase (an indicator of pancreatic injury) as well as lactate (an indicator of tissue hypoxia). None of the tyrosine kinase inhibitors tested had a significant effect on the rise in the serum levels of urea, but the tyrphostins AG126, AG556 or Al significantly attenuated the rises in the serum levels of creatinine caused by LPS. In addition, all tyrphostins and genistein attenuated the liver injury/failure, the pancreatic injury, the hypoglycaemia and the lactic acidosis caused by LPS. In contrast, daidzein did not reduce the organ injury/dysfunction or the lactic acidosis caused by LPS.5 Injection of LPS resulted (within 90 min) in a substantial increase in the serum level of tumour necrosis factor alpha (TNF alpha), which was attenuated by pretreatment of LPS-rats with any of the tyrphostins used. Genistein, but not daidzein, also reduced the rise in the serum levels of TNF alpha caused by LPS. Endotoxaemia for 6 h also resulted in a substantial increase in the expression of iNOS and COX-2 protein and activity in the lung, which was attenuated by pretreatment of LPS-rats with the tyrphostins AG126, AG556 or genistein, but not by daidzein.6 Thus, tyrphostins (AG126, AG490, AG556, AG1641 or Al) and genistein, but not daidzein (inactive analogue of genistein), prevent the (i) circulatory failure, (ii) the multiple organ dysfunction (liver and pancreatic dysfunction/injury, lactacidosis, hypoglycaemia), as well as (iii) the induction of iNOS and COX-2 protein and activity in rats with endotoxic shock.