Table_2_Anesthesia-Sepsis-Associated Alterations in Liver Gene Expression Profiles and Mitochondrial Oxidative Phosphorylation Complexes.docx

Background: Hepatic dysfunction plays a major role in adverse outcomes in sepsis. Volatile anesthetic agents may protect against organ dysfunction in the setting of critical illness and infection. The goal of this study was to study the impact of Sepsis-inflammation on hepatic subcellular energetics in animals anesthetized with both Propofol (intravenous anesthetic agent and GABA agonist) and Isoflurane (volatile anesthetic i.e., VAA).
Methods: Sprague-Dawley rats were anesthetized with Propofol or isoflurane. Rats in each group were randomized to celiotomy and closure (control) or cecal ligation and puncture “CLP” (Sepsis-inflammation) for 8 h.
Results: Inflammation led to upregulation in hepatic hypoxia-inducible factor-1 in both groups. Rats anesthetized with isoflurane also exhibited increases in bcl-2, inducible nitric oxide synthase, and heme oxygenase-1(HO-1) during inflammation, whereas rats anesthetized with Propofol did not. In rats anesthetized with isoflurane, decreased mRNA, protein (Complex II, IV, V), and activity levels (Complex II/III,IV,V) were identified for all components of the electron transport chain, leading to a decrease in mitochondrial ATP. In contrast, in rats anesthetized with Propofol, these changes were not identified after exposure to inflammation. RNA-Seq and real-time quantitative PCR (qPCR) expression analysis identified a substantial difference between groups (isoflurane vs. Propofol) in mitogen-activated protein kinase (MAPK) related gene expression following exposure to Sepsis-inflammation.
Conclusions: Compared to rats anesthetized with Propofol, those anesthetized with isoflurane exhibit more oxidative stress, decreased oxidative phosphorylation protein expression, and electron transport chain activity and increased expression of organ-protective proteins.

## 背景
肝功能不全（hepatic dysfunction）是脓毒症（sepsis）不良预后的关键影响因素。挥发性麻醉剂（volatile anesthetic agents）在重症疾病与感染情境下，或可对器官功能不全发挥保护作用。本研究旨在探究脓毒症炎症对分别接受丙泊酚（Propofol，静脉麻醉剂及γ-氨基丁酸受体激动剂）与异氟烷（Isoflurane，挥发性麻醉剂即VAA）麻醉的动物的肝亚细胞能量代谢的影响。

## 方法
将斯普拉格-道利（Sprague-Dawley, SD）大鼠随机分为两组，分别以丙泊酚或异氟烷进行麻醉。每组大鼠再被随机分配至对照亚组（剖腹术及关腹）或盲肠结扎穿刺（cecal ligation and puncture, CLP，脓毒症炎症模型）亚组，造模持续时长为8小时。

## 结果
炎症刺激可使两组大鼠的肝组织缺氧诱导因子-1（hypoxia-inducible factor-1）表达上调。异氟烷麻醉组大鼠在炎症刺激下，其B细胞淋巴瘤因子2（bcl-2）、诱导型一氧化氮合酶（inducible nitric oxide synthase）及血红素氧合酶-1（heme oxygenase-1, HO-1）的表达水平均升高，而丙泊酚麻醉组未出现该变化。在异氟烷麻醉组大鼠中，电子传递链（electron transport chain）各组分的mRNA、蛋白（复合物Ⅱ、Ⅳ、Ⅴ）及活性（复合物Ⅱ/Ⅲ、Ⅳ、Ⅴ）水平均显著下降，进而导致线粒体三磷酸腺苷（mitochondrial ATP）生成减少。与之相反，丙泊酚麻醉组大鼠在炎症刺激后未观察到上述异常变化。通过RNA测序（RNA-Seq）与实时定量聚合酶链反应（real-time quantitative PCR, qPCR）进行表达分析后发现，脓毒症炎症刺激后，两组（异氟烷组vs丙泊酚组）的丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）相关基因表达存在显著差异。

## 结论
与丙泊酚麻醉的大鼠相比，异氟烷麻醉的大鼠氧化应激（oxidative stress）水平更高，氧化磷酸化相关蛋白表达与电子传递链活性更低，且器官保护蛋白的表达水平更高。