线粒体调控“双通路”及PARP-1基因抑制对严重脓毒症所致急性胰岛素抵抗的作用

Acute insulin resistance (AIR) significantly increases the death risk of the patients with severe sepsis (SS) with an undetermined pathogenetic mechanism. Although it shares some similarities with the pathogenesis of chronic insulin resistance (CIR), its own characteristics is crucial for the treatment due to the obviously differences in the risk factors and outcome between them. From the early data of our research, we found there was significant difference in the presentaiton of mitochondria dysfunction between them: AIR presented with mitochondrial oxidative stress dysfunction, while CIR presented with both mitochondrial oxidative stress dysfunction and the mitochondrial biogenesis disorders. We will work on the double molecular regulatory pathways of mitochondria (oxidative regulatory pathway and biogenesis regulatory pathway), and hypothesize that there are different expression levels and following effects of the double pathways between the pathogenesis of AIR and CIR. The over activation of Poly [ADP-ribose] polymerase 1 (PARP-1) would cause the exhaustion of NAD+ and ATP, which could further lead to mitochondrial dysfunction and cell death. Inhibition of PARP-1 was proved to increase the mitochondria metabolism through the activation of Sirutin-1 (SIRT1). Here, we hypothesize that the selective inhibition of PARP-1 will ameliorate mitochondrial dysfunction and the degree of acute insulin resistance, and will further delay the deterioration and improve the prognosis in the patients with SS.

急性胰岛素抵抗（AIR）显著增加严重脓毒症（SS）患者死亡风险，危害严重。其发生机制仍未阐明，虽可能与慢性胰岛素抵抗（CIR）的发生存在相通之处，但二者病因、转归截然不同，探讨其自身特点至关重要。我们的前期实验数据提示，不同胰岛素抵抗状态中（AIR、CIR）线粒体功能障碍表现形式不同：前者仅有氧化应激损伤，后者则氧化应激损伤和合成障碍并存。我们拟在分子调控水平深入研究并假设：线粒体氧化应激和合成调控的“双分子通路”在不同胰岛素抵抗状态下表达水平及后续效应不尽相同。过度活化的聚二磷酸腺苷核糖聚合酶1（PARP-1）可耗竭NAD+和ATP，使细胞出现线粒体功能障碍甚至死亡，而抑制PARP-1可通过激活线粒体“双通路”关键调控因子去乙酰化酶1（SIRT1）而改善线粒体代谢。我们进一步假设：选择性抑制PARP-1能通过SIRT1介导途径提高线粒体功能、改善AIR状态，并延缓SS恶化进展，改善预后。

严重脓毒症（SS） 是ICU常见病，并可伴发急性胰岛素抵抗（AIR），医疗花费及致残率、病死率均较高，位居成人死亡原因第四位。探讨其发生发展机制和不良预后危险因素的是学科当前研究的热点，线粒体损伤可能深入其中。本研究拟探讨线粒体氧化应激和合成调控的“双分子通路”在SS所致线粒体损伤中发挥的作用，选择性抑制聚二磷酸腺苷核糖聚合酶1（PARP-1）能否通过线粒体“双通路”来发挥改善线粒体代谢和脏器功能，并拟在临床病人中揭示病情持续进展并出现不良预后的重要危险因素。本研究发现：1、SS伴发AIR小鼠出现明显的肝脏线粒体功能障碍和结构损伤。同时，此类小鼠肝脏线粒体合成上游因子表达水平显著降低，并出现明显的氧化应激损伤和炎症反应；2、PARP-1抑制可以有效缓解脓毒症肝脏线粒体功能障碍和结构损伤，改善线粒体呼吸复合体的呼吸容量，提高线粒体ATP产量，增加线粒体膜电位水平，减少线粒体肿胀和线粒体自噬；PARP-1抑制可能通过对肝脏线粒体生物合成通路、氧化应激通路和炎症反应通路的正向作用而对线粒体发挥靶向调节作用，从而改善脓毒症继发的肝脏线粒体的损伤，改善脏器功能；3、与组织缺血低灌注和线粒体损伤相关的临床指标，如缺血修饰白蛋白、早期乳酸面积等，均是病情进展并出现不良预后的重要危险因子；对于血流感染导致的SS人群，有其自己特殊的临床特征和危险因素。本研究发现了PARP-1抑制及线粒体调控“双通路”在SS伴发AIR发生中的重要作用，同时也揭示了临床病人出现不良预后的重要危险因素，为该疾病的治疗提供了新的干预方向。