Impact of a novel phosphoinositol-3 kinase inhibitor in preventing mitochondrial DNA damage and damage-associated molecular pattern accumulation: Results from the Biochronicity Project.
Impact of a novel phosphoinositol-3 kinase inhibitor in preventing mitochondrial DNA damage and damage-associated molecular pattern accumulation: Results from the Biochronicity Project.
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DOI：
10.1097/ta.0000000000001593
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Martin MJ
中科院分区：
文献类型：
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作者：
Black GE;Sokol KK;Moe DM;Simmons JD;Muscat D;Pastukh V;Capley G;Gorodnya O;Ruchko M;Roth MB;Gillespie M;Martin MJ
尽管对严重受伤患者的治疗有所改善，但多器官功能障碍综合征（MODS）的发展仍然是创伤性休克的一种病态并发症。 MODS 的关键属性之一是一场深刻的生物能学危机，但人们对其调节因素和机制知之甚少。我们假设，使用实验性磷酸肌醇-3 激酶 (PI3-K) 抑制剂 LY294002 (LY) 进行代谢解偶联，可以防止导致线粒体 DNA (mtDNA) 损伤产生和 mtDNA 损伤相关分子模式 (DAMP) 释放的线粒体异常。使用 LY（一种非选择性 PI3-K 抑制剂）对 16 头猪进行了研究。动物被分配到仅创伤组（TO，n = 3）、仅LY药物组（LYO，n = 3）和实验组（n = 10）、创伤+药物组（LY + T）。两个创伤组均接受了剖腹手术、35% 的出血、严重的缺血再灌注损伤和方案复苏。监测了一系列血流动力学、实验室、组织学和生物能学参数。使用 Southern blot 分析确定肺、肝和肾中的线粒体 DNA 损伤，而血浆 mtDNA DAMP 分析则使用 mtDNA D 环区域 200 bp 序列的聚合酶链反应扩增。相对于对照动物，H+I/R（出血和缺血/再灌注）导致肝、肾、心血管和肺功能严重的、时间依赖性的下降，并伴有严重的酸中毒和乳酸积累，表明生物能不足。 H-I/R 动物在所有研究的器官中都表现出明显的氧化 mtDNA 损伤，其中肝脏的损伤最明显。线粒体DNA损伤伴随着血浆中mtDNA DAMP的积累。用 LY 预处理 H + I/R 动物会导致严重的代谢抑制，O2 消耗和 CO2 产生减少约 50%。此外，它还可以预防器官和生物能功能障碍，并与血浆 mtDNA DAMP 显着降低至对照动物的水平相关。这些发现表明，麻醉猪中的 H + I/R 损伤伴有 MODS 和显着的线粒体生物能功能障碍，包括氧化 mtDNA 损伤和 mtDNA DAMP 在血浆中的积累。 PI3-K 抑制剂 LY 对这些变化的抑制表明，药理学诱导的代谢解偶联可能构成一种新的药理学策略，以防止 mtDNA 损伤和 DAMP 释放，并预防或治疗创伤相关 MODS。治疗研究，III级。
Despite improvements in the management of severely injured patients, development of multiple organ dysfunction syndrome (MODS) remains a morbid complication of traumatic shock. One of the key attributes of MODS is a profound bioenergetics crisis, for which the mediators and mechanisms are poorly understood. We hypothesized that metabolic uncoupling using an experimental phosphoinositol-3 kinase (PI3-K) inhibitor, LY294002 (LY), may prevent mitochondrial abnormalities that lead to the generation of mitochondrial DNA (mtDNA) damage and the release of mtDNA damage-associated molecular patterns (DAMPs). Sixteen swine were studied using LY, a nonselective PI3-K inhibitor. Animals were assigned to trauma only (TO, n = 3), LY drug only (LYO, n = 3), and experimental (n = 10), trauma + drug (LY + T) groups. Both trauma groups underwent laparotomy, 35% hemorrhage, severe ischemia-reperfusion injury, and protocolized resuscitation. A battery of hemodynamic, laboratory, histological, and bioenergetics parameters were monitored. Mitochondrial DNA damage was determined in lung, liver, and kidney using Southern blot analyses, whereas plasma mtDNA DAMP analysis used polymerase chain reaction amplification of a 200-bp sequence of the mtDNA D-loop region. Relative to control animals, H + I/R (hemorrhage and ischemia/reperfusion) produced severe, time-dependent decrements in hepatic, renal, cardiovascular, and pulmonary function accompanied by severe acidosis and lactate accumulation indicative of bioenergetics insufficiency. The H-I/R animals displayed prominent oxidative mtDNA damage in all organs studied, with the most prominent damage in the liver. Mitochondrial DNA damage was accompanied by accumulation of mtDNA DAMPs in plasma. Pretreatment of H + I/R animals with LY resulted in profound metabolic suppression, with approximately 50% decreases in O2 consumption and CO2 production. In addition, it prevented organ and bioenergetics dysfunction and was associated with a significant decrease in plasma mtDNA DAMPs to the levels of control animals. These findings show that H + I/R injury in anesthetized swine is accompanied by MODS and by significant mitochondrial bioenergetics dysfunction, including oxidative mtDNA damage and accumulation in plasma of mtDNA DAMPs. Suppression of these changes with the PI3-K inhibitor LY indicates that pharmacologically induced metabolic uncoupling may comprise a new pharmacologic strategy to prevent mtDNA damage and DAMP release and prevent or treat trauma-related MODS. Therapeutic study, level III.