陈胜阳;张永强;刘俊;刘国泽;田建民;岳修勤;

• 1:新乡医学院第一附属医院麻醉科

摘要(Abstract)：

目的考察右美托咪定(Dex)对脂多糖(LPS)诱导的大鼠急性肺损伤(ALI)的影响,并探讨可能与PI3K/Akt信号通路改变的相关机制。方法将80只SD大鼠根据建模方法随机分为5组:对照组、模型组、Dex低剂量组、Dex高剂量组、Dex+LY294002组,建模24 h时处死并分离肺组织,观察组织病理切片,检查肺水肿程度及微血管通透性,采用Westernblotting法检测Akt及其磷酸化蛋白以及线粒体凋亡信号相关蛋白的表达水平,检查线粒体细胞色素C、膜电位及ATP含量,并用电镜观察线粒体形态,采用流式细胞术检测肺组织细胞凋亡情况,采用DCFH-DA探针荧光显微镜法检测细胞内的活性氧(ROS)水平。结果 LPS滴注24 h后,病理切片表现有明显的ALI特征,Dex在50μg/kg剂量时可明显改善LPS诱导的ALI病理特征;以对照组为参照,p-Akt(Thr308)与p-Akt(Ser473)的相对表达量模型组未发生明显变化,Dex组则均显著增高(P<0.001),在Dex+LY294002组的表达水平较Dex组显著降低(P<0.001);模型组的Bax与Bcl-2蛋白较对照组的相对表达量分别显著升高与降低(P<0.001),Dex组分别降低与升高至接近对照组水平,Dex+LY294002组又分别回升与回降;对照组、模型组、Dex组、Dex+LY294002组的肺组织细胞凋亡率分别为2.4%、19.5%、6.7%、13.1%;各组的ROS水平变化与肺组织细胞凋亡情况一致性良好。结论 Dex可通过激活PI3K/Akt信号通路减轻LPS诱导的肺组织细胞凋亡及线粒体凋亡信号激活,继而改善ALI,发挥肺保护作用。

关键词(KeyWords)： 右美托咪定;急性肺损伤;PI3K/Akt通路;细胞凋亡

Abstract:

Keywords:

基金项目(Foundation): 河南省医学科技攻关计划项目（2018020351）

作者(Author): 陈胜阳;张永强;刘俊;刘国泽;田建民;岳修勤;

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DOI:

参考文献(References)：

• [1] Rubenfuld G D, Herridge M S. Epidemimology and outcomes of acute lung injury[J]. Chest, 2007, 131(2):554-562.
• [2] Liu C J, Yang J X, Fu W J, et al. Coactivation of the PI3K/Akt and ERK signaling pathways in PCB153-induced NF-κB activation and caspase inhibition[J].Toxicol Appl Pharmacol, 2014, 277(3):270-278.
• [3] Markou T, Chambers D J. Lung injury after simulated cardiopulmonary bypass in an isolated perfused rat lung preparation:Role of mitogen-activated protein kinase/Akt signaling and the effects of theophylline[J]. J Thorac Cardiovasc Surg, 2014, 148(5):2335-2344.
• [4] Chang J S, Lin H J, Deng J S, et al. Preventive effects of velvet antler(Cervus elaphus)against lipopolysaccharideinduced acute lung injury in mice by inhibiting MAPK/NF-κB activation and inducing AMPK/Nrf2 pathways[J].Evid Based Complement Alternat Med, 2018, 2018:2870503.
• [5] Lee J, Kosaras B, del Signore S J, et al. Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington's disease mice[J]. Acta Neuropathol, 2011, 121(4):487-498.
• [6] Liang D H, Choi D S, Ensor J E, et al. The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair[J]. Cancer Lett, 2016,376(2):249-258.
• [7] Xu Y Z, Zhang R Y, Li C L, et al. Dexmedetomidine attenuates acute lung injury induced by lipopolysaccharide in mouse through inhibition of MAPK pathway[J]. Fundam Clin Pharmacol, 2015, 29(5):462-471.
• [8] Gao S Q, Wang Y L, Zhao J, et al. Effects of dexmedetomidine pretreatment on heme oxygenase-1 expression and oxidative stress during one-lung ventilation[J]. Int J Clin Exp Pathol, 2015, 8(3):3144-3149.
• [9] Cui J, Zhao H L, Wang C Y, et al. Dexmedetomidine attenuates oxidative stress induced lung alveolar epithelial cell apoptosis in vitro[J]. Oxid Med Cell Longev, 2015,2015:358396.
• [10] Jiang Y X, Dai Z L, Zhang X P, et al. Dexmedetomidine alleviates pulmonary edema by upregulating AQP1 and AQP5 expression in rats with acute lung injury induced by lipopolysaccharide[J]. J Huazhong Univ Sci Technol:Med Sci, 2015, 35(5):684-688.
• [11] Zhang Q Y, Wu D, Yang Y, et al. Effects of dexmedetomidine on the protection of hyperoxia-induced lung injury in newborn rats[J]. Int J Clin Exp Pathol, 2015, 8(6):6466-6473.
• [12] Wu X J, Song X M, Li N T, et al. Protective effects of dexmedetomidine on blunt chest trauma-induced pulmonary contusion in rats[J]. J Trauma Acute Care Surg, 2013,74(2):524-530.
• [13] Martini M, de Santis M C, Braccini L, et al. PI3K/AKT signaling pathway and cancer:An updated review[J].Ann Med, 2014, 46(6):372-383.
• [14] Martelli A M, Tabellini G, Bressanin D, et al. The emerging multiple roles of nuclear Akt[J]. Biochim Biophys Acta, 2012, 1823(12):2168-2178.
• [15] Tsuchiya A, Kanno T, Nishizaki T. PI3 kinase directly phosphorylates Akt1/2 at Ser473/474 in the insulin signal transduction pathway[J]. J Endocrinol, 2014, 220(1):49-59.
• [16] Risso G, Blaustein M, Pozzi B, et al. Akt/PKB:One kinase, many modifications[J]. Biochem J, 2015, 468(2):203-214.
• [17] Lai J P, Bao S Y, Davis I C, et al. Inhibition of the phosphatase PTEN protects mice against oleic acidinduced acute lung injury[J]. Br J Pharmacol, 2009,156(1):189-200.
• [18] Zhao S P, Wu J, Zhang L M, et al. Post-conditioning with sevoflurane induces heme oxygenase-1 expression via the PI3K/Akt pathway in lipopolysaccharide-induced acute lung injury[J]. Mol Med Rep, 2014, 9(6):2435-2440.
• [19] Zhang W, Zhang J Q, Meng F M, et al. Dexmedetomidine protects against lung ischemia-reperfusion injury by the PI3K/Akt/HIF-1αsignaling pathway[J]. J Anesth, 2016,30(5):826-833.
• [20] Sureshbabu A, Syed M, Das P, et al. Inhibition of regulatory-associated protein of mechanistic target of rapamycin prevents hyperoxia-induced lung injury by enhancing autophagy and reducing apoptosis in neonatal mice[J]. Am J Respir Cell Mol Biol, 2016, 55(5):722-735.
• [21] Aouacheria A, Baghdiguian S, Lamb H M, et al.Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins[J]. Neurochem Int, 2017,109:141-161.
• [22] Li J L, Wu H H, Xue G, et al. 17β-oestradiol protects primary-cultured rat cortical neurons from ketamineinduced apoptosis by activating PI3K/Akt/bcl-2 signalling[J]. Basic Clin Pharmacol Toxicol, 2013, 113(6):411-418.
• [23] Meng Y, Wang W W, Kang J S, et al. Role of the PI3K/AKT signalling pathway in apoptotic cell death in the cerebral cortex of streptozotocin-induced diabetic rats[J]. Exp Ther Med, 2017, 13(5):2417-2422.
• [24] Liu J, Jiang X W, Zhang Q, et al. Neuroprotective effects of Kukoamine A against cerebral ischemia via antioxidant and inactivation of apoptosis pathway[J]. Neurochem Int,2017, 107:191-197.
• [25] Lindblom R, Higgins G, Coughlan M, et al. Targeting mitochondria and reactive oxygen species-driven pathogenesis in diabetic nephropathy[J]. Rev Diabet Stud, 2015, 12(1/2):134-156.
• [26] Wu Y Y, Xue B, Li X J, et al. Puerarin prevents high glucose-induced apoptosis of Schwann cells by inhibiting oxidative stress[J]. Neural Regen Res, 2012, 7(33):2583-2591.