Increased O-linked beta-N-acetylglucosamine levels on proteins improves survival, reduces inflammation and organ damage 24 hours after trauma-hemorrhage in rats.
Increased O-linked beta-N-acetylglucosamine levels on proteins improves survival, reduces inflammation and organ damage 24 hours after trauma-hemorrhage in rats.
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DOI：
10.1097/ccm.0b013e3181cb10b3
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发表时间：
2010-02
影响因子：
8.8
通讯作者：
Chatham JC
中科院分区：
文献类型：
--
作者：
Nöt LG;Brocks CA;Vámhidy L;Marchase RB;Chatham JC
我们先前已经表明，通过不同机制增加蛋白O-连接的β-N-乙酰葡萄糖胺（O-GlcNAc）水平可减少创伤-出血（T-H）后2小时的炎症反应并改善器官功能。该研究的目的是评估T-H后24小时O-GlcNAc水平对存活、炎症和器官损伤的影响。前瞻性随机对照研究。动物研究实验室。雄性成年Sprague-Dawley大鼠。对禁食过夜的动物进行假手术（SH）或（T-H），并在复苏阶段期间接受葡糖胺（270 mg/Kg，GlcN）以增加O-GlcNAc合成或O-（2-乙酰氨基-2-脱氧-D-吡喃葡萄糖亚基）氨基N-苯基氨基甲酸酯（7 mg/Kg，PUGNAc）以抑制O-GlcNAc去除，或甘露醇作为对照（CON）。生存随访24小时。对存活大鼠实施安乐死，并评估炎症反应和终末器官损伤。与对照相比，GlcN和PUGNAc均增加24小时存活（CON：53%，GN：85%，PUGNAc：86%，对数秩检验，p<0.05）。PUGNAc可减弱T-H诱导的血清IL-6水平升高（SH：8±6，CON：181±36，PUGNAc：42±22 pg/mL，p<0.05），ALT（SH：95±14，CON：297±56，PUGNAc：126±21 IU，p<0.05），AST（SH：536±110，CON：1661±215，PUGNAc：897±155 IU，p<0.05）和LDH（SH：160±18，CON：1499±311，PUGNAc：357±99 IU，p<0.05）;然而，GlcN对这些血清参数没有影响。此外，PUGNAc而不是GlcN维持了肝和肺中的O-GlcNAc水平，并显著减弱了肝中NF-κB DNA的活化。在肝脏和心脏中，PUGNAc处理组中增加的iNOS表达也减弱。这些结果表明，用GlcN或PUGNAc增加O-GlcNAc改善了T-H后的24小时存活。然而，仅PUGNAc治疗显著减弱随后的组织损伤和炎症反应，表明抑制O-GlcNAc去除可能代表治疗低血容量性休克的新治疗方法。
We have previously shown that increasing protein O-linked β-N-acetylglucosamine (O-GlcNAc) levels by different mechanisms reduced inflammatory responses and improved organ function 2 hours after trauma-hemorrhage (T-H). The aim of the study was to evaluate the effects of O-GlcNAc levels on survival, inflammation and organ damage 24 hours after T-H. Prospective, randomized, controlled study. Animal research laboratory. Male, adult Sprague-Dawley rats. Overnight fasted animals were subjected to either sham surgery (SH) or (T-H) and during the resuscitation phase received glucosamine (270 mg/Kg, GlcN) to increase O-GlcNAc synthesis or O-(2-Acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenyl Carbamate, (7mg/Kg, PUGNAc) to inhibit O-GlcNAc removal, or mannitol as control (CON). Survival was followed up for 24 hours. Surviving rats were euthanized and inflammatory responses, and end organ injuries were assessed. Both GlcN and PUGNAc increased 24 hours survival compared to controls (CON: 53%, GN: 85%, PUGNAc: 86%, logrank test, p<0.05). PUGNAc attenuated the T-H induced increase in serum IL-6 (SH: 8±6, CON: 181±36, PUGNAc: 42±22 pg/mL, p<0.05), ALT (SH: 95±14, CON: 297±56, PUGNAc: 126±21 IU, p<0.05), AST (SH: 536±110, CON: 1661±215, PUGNAc: 897±155 IU, p<0.05) and LDH (SH: 160±18, CON: 1499±311, PUGNAc: 357±99 IU, p<0.05); however, GlcN had no effect on these serum parameters. Furthermore, PUGNAc but not GlcN maintained O-GlcNAc levels in liver and lung and significantly attenuated the NF-κB DNA activation in the liver. In the liver and heart, increased iNOS expression was also attenuated in the PUGNAc treated group. These results demonstrate that increasing O-GlcNAc with either GlcN or PUGNAc improved 24 hour survival after T-H. However, only PUGNAc treatment attenuated significantly the subsequent tissue injury and inflammatory responses, suggesting that inhibition of O-GlcNAc removal may represent a new therapeutic approach for the treatment of hypovolemic shock.