Sirtuin 1 Agonist Minimizes Injury and Improves the Immune Response Following Traumatic Shock.
Sirtuin 1 Agonist Minimizes Injury and Improves the Immune Response Following Traumatic Shock.
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Sirtuin 1 激动剂可最大限度地减少损伤并改善创伤性休克后的免疫反应。
DOI：
10.1097/shk.0000000000000412
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Zuckerbraun,BrianS
中科院分区：
文献类型：
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作者：
Luciano,JasonA;Kautza,Benjamin;Darwiche,Sophie;Martinez,Silvia;Stratimirovic,Sladjana;Waltz,Paul;Sperry,Jason;Rosengart,Matthew;Shiva,Sruti;Zuckerbraun,BrianS
从创伤性损伤中存活需要协调和控制的炎症和免疫反应。对应激的线粒体和代谢反应已被证明在这些炎症和免疫反应中起作用。我们假设通过sirtuin 1激动剂增加线粒体生物合成可以减少组织损伤并部分改善创伤后的免疫抑制。对C57 B1/6小鼠进行多发性创伤模型。小鼠在创伤前2天通过经口灌胃给予100 mg/kg/天的沉默调节蛋白1激动剂Srt 1720预处理，并延长至动物处死当天，或者在创伤前48 h通过尾静脉水动力注射给予过氧化物酶体增殖物激活受体γ共激活因子1α（PGC 1 α）siRNA预处理。除了脾细胞增殖能力和细菌清除外，还测量了线粒体功能和生物发生的标志物。Srt 1720可改善创伤后线粒体生物合成、线粒体功能和复合物IV活性（P< 0.05），而PGC 1 α敲低可导致线粒体功能障碍加重（P< 0.05）。线粒体功能的这些变化与肝损伤的严重程度改变有关，在用srt 1720处理的小鼠中观察到血清丙氨酸转氨酶水平显著降低。脾细胞增殖能力和腹腔内细菌清除率作为创伤出血后整体免疫功能的标志物进行评价。Srt 1720处理使创伤诱导的脾细胞增殖降低最小化（P< 0.05），而PGC 1 α siRNA处理导致细菌清除减少。PGC 1 α信号通路是线粒体功能和生物合成的重要调节因子，可用于保护肝损伤，并最大限度地减少创伤出血后的免疫抑制。
Survival from traumatic injury requires a coordinated and controlled inflammatory and immune response. Mitochondrial and metabolic responses to stress have been shown to play a role in these inflammatory and immune responses. We hypothesized that increases in mitochondrial biogenesis via a sirtuin 1 agonist would decrease tissue injury and partially ameliorate the immunosuppression seen following trauma. C57Bl/6 mice were subjected to a multiple trauma model. Mice were pretreated with either 100 mg/kg per day of the sirtuin 1 agonist, Srt1720, via oral gavage for 2 days prior to trauma and extended until the day the animals were killed, or they were pretreated with peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) siRNA via hydrodynamic tail vein injection 48 h prior to trauma. Markers for mitochondrial function and biogenesis were measured in addition to splenocyte proliferative capacity and bacterial clearance. Srt1720 was noted to improve mitochondrial biogenesis, mitochondrial function, and complex IV activity following traumatic injury (P< 0.05), whereas knockdown of PGC1α resulted in exacerbation of mitochondrial dysfunction (P< 0.05). These changes in mitochondrial function were associated with altered severity of hepatic injury with significant reductions in serum alanine aminotransferase levels seen in mice treated with srt1720. Splenocyte proliferative capacity and intraperitoneal bacterial clearance were evaluated as markers for overall immune function following trauma-hemorrhage. Treatment with Srt1720 minimized the trauma-induced decreases in splenocyte proliferation (P< 0.05), whereas treatment with PGC1α siRNA led to diminished bacterial clearance. The PGC1α signaling pathway is an important regulator of mitochondrial function and biogenesis, which can potentially be harnessed to protect against hepatic injury and minimize the immunosuppression that is seen following trauma-hemorrhage.