Inhibition of glycogen synthase kinase (GSK)-3-尾 improves liver microcirculation and hepatocellular function after hemorrhagic shock

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• 作者：Lena Jellestad ; Tobias Fink ; Sascha Pradarutti ; Darius Kubulus ; Beate Wolf ; Inge Bauer ; Chris Thiemermann ; Hauke Rensing
• 关键词：GSK-3 ; Hemorrhagic shock ; Intravital microscopy ; Cytokine ; Plasma disappearance rate
• 刊名：European Journal of Pharmacology
• 出版年：5 February, 2014
• 年：2014
• 卷：724
• 期：Complete
• 页码：175-184
• 全文大小：1238 K

文摘

Ischemia and reperfusion may cause liver injury and are characterized by hepatic microperfusion failure and a decreased hepatocellular function. Inhibition of glycogen synthase kinase (GSK)-3尾, a serine-threonine kinase that has recently emerged as a key regulator in the modulation of the inflammatory response after stress events, may be protective in conditions like sepsis, inflammation and shock. Therefore, aim of the study was to assess the role of GSK-3尾 in liver microcirculation and hepatocellular function after hemorrhagic shock and resuscitation (H/R). Anesthetized male Sprague-Dawley rats underwent pretreatment with Ringer麓s solution, vehicle (DMSO) or TDZD-8 (1 mg/kg), a selective GSK-3尾 inhibitor, 30 min before induction of hemorrhagic shock (mean arterial pressure 35卤5 mmHg for 90 min) and were resuscitated with shed blood and Ringer麓s solution (2 h). 5 h after resuscitation hepatic microcirculation was assessed by intravital microscopy. Propidium iodide (PI) positive cells, liver enzymes and alpha-GST were measured as indicators of hepatic injury. Liver function was estimated by assessment of indocyanine green plasma disappearance rate. H/R led to a significant decrease in sinusoidal diameters and impairment of liver function compared to sham operation. Furthermore, the number of PI positive cells in the liver as well as serum activities of liver enzymes and alpha-GST increased significantly after H/R. Pretreatment with TDZD-8 prevented the changes in liver microcirculation, hepatocellular injury and liver function after H/R. A significant rise in the plasma level of IL-10 was observed. Thus, inhibition of GSK-3尾 before hemorrhagic shock modulates the inflammatory response and improves hepatic microcirculation and hepatocellular function.