Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock
Decrease of the inflammatory response and induction of the Akt/protein kinase B pathway by poly-(ADP-ribose) polymerase 1 inhibitor in endotoxin-induced septic shock
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DOI：
10.1016/s0006-2952(03)00077-7
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发表时间：
2003-04-15
影响因子：
5.8
通讯作者：
Sumegi, B
中科院分区：
文献类型：
--
作者：
Veres, B;Gallyas, F;Sumegi, B
由于抗炎药、抗凝血剂、抗氧化剂等在危重患者中缺乏疗效，人们开始转向开发替代治疗方法。由于核酶多聚（adp -核糖）聚合酶（PARP）抑制剂被发现在许多与氧化应激相关的病理生理条件下是有益的，并且PARP-1敲除小鼠被证明对细菌脂多糖（LPS）诱导的脓毒性休克具有抗性，PARP抑制剂是这种作用的候选物。本研究研究了强效PARP-1抑制剂PJ34对lps诱导（20 mg/kg, i.p）小鼠脓毒性休克的保护作用机制。我们通过磁共振成像在背部皮下区域、肾脏周围的腹部区域和肠腔内证明了显著的炎症反应。我们发现肝脏和小肠内有坏死和凋亡的组织学改变以及血管阻塞。此外，我们检测到lps处理小鼠血清中肿瘤坏死因子- α水平升高，肝脏中核因子κ B活化。在LPS刺激前用PJ34 （10 mg/kg, i.p.p）预处理动物，除了使动物免于LPS诱导的死亡外，还可能通过激活磷脂酰肌醇3-激酶- akt /蛋白激酶B细胞保护通路来减轻这些变化。(C) 2003爱思唯尔科学有限公司版权所有。
The lack of efficacy of anti-inflammatory drugs, anti-coagulants, anti-oxidants, etc. in critically ill patients has shifted interest towards developing alternative treatments. Since inhibitors of the nuclear enzyme poly-(ADP-ribose) polymerase (PARP) were found to be beneficial in many pathophysiological conditions associated with oxidative stress and PARP-1 knock-out mice proved to be resistant to bacterial lipopolysaccharide (LPS)-induced septic shock, PARP inhibitors are candidates for such a role. In this study, the mechanism of the protective effect of a potent PARP-1 inhibitor, PJ34 was studied in LPS-induced (20 mg/kg, i.p.) septic shock in mice. We demonstrated a significant inflammatory response by magnetic resonance imaging in the dorsal subcutaneous region, in the abdominal regions around the kidneys and in the inter-intestinal cavities. We have found necrotic and apoptotic histological changes as well as obstructed blood vessels in the liver and small intestine. Additionally, we have detected elevated tumor necrosis factor-alpha levels in the serum and nuclear factor kappa B activation in liver of LPS-treated mice. Pre-treating the animals with PJ34 (10 mg/kg, i.p.), before the LPS challenge, besides rescuing the animals from LPS-induced death, attenuated all these changes presumably by activating the phosphatidylinositol 3-kinase-Akt/protein kinase B cytoprotective pathway. (C) 2003 Elsevier Science Inc. All rights reserved.