Simvastatin decreases hyperbaric oxygen-induced acute lung injury by upregulating eNOS
Simvastatin decreases hyperbaric oxygen-induced acute lung injury by upregulating eNOS
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辛伐他汀通过上调 eNOS 减少高氧引起的急性肺损伤
DOI：
10.1152/ajplung.00520.2016
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发表时间：
2018-02-01
影响因子：
4.9
通讯作者：
You, Pu
中科院分区：
文献类型：
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作者：
Bao, Xiao-Chen;Mao, An-Rong;You, Pu
他汀类药物是3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶的竞争性抑制剂，不仅能降低血胆固醇，而且在多种疾病中发挥多种有益作用。然而，他汀类药物在高压氧(HBO)诱导的急性肺损伤(ALI)中的作用尚未见报道。本研究首次探讨了辛伐他汀对高压氧诱导的8~9周龄C57BL/6小鼠急性肺损伤的影响。小鼠暴露于0.23 Mpa[=2.3大气绝对值(ATA)]高氧(-gt；=95%O-2)中6h。收集肺组织、血清和支气管肺泡灌洗液(BALF)以分析促凋亡蛋白、低密度脂蛋白胆固醇(LDL-C)水平和肺部炎症。辛伐他汀治疗显著降低肺通透性、血清低密度脂蛋白水平、组织细胞凋亡和炎症。但辛伐他汀对抗氧化酶活性、烟酰胺腺嘌呤二核苷酸磷酸氧化酶4(NADPH4)表达和Akt磷酸化水平无影响。此外，我们还研究了内皮型一氧化氮合酶(ENOS)在辛伐他汀保护中的作用，方法是用NG-硝基精氨酸甲酯(L，20 mg/kg)抑制eNOS的活性。结果显示，辛伐他汀对高压氧诱导的ALI(抗炎、抗细胞凋亡、降脂、降低肺通透性)的有利作用被逆转。这些结果表明，辛伐他汀通过上调eNOS的表达来抑制高压氧所致的肺水肿、通透性、炎症和细胞凋亡，辛伐他汀可能是治疗高压氧长期暴露的有效方法。
Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase competitive inhibitors, not only lower blood cholesterol but also exert pleiotropic and beneficial effects in various diseases. However, the effects of statins on acute lung injury (ALI) induced by hyperbaric oxygen (HBO) have not been investigated. The present study is the first to investigate the effects of simvastatin in ALI induced by HBO in 8-to 9-wk-old C57BL/6 mice exposed to 0.23 MPa [= 2.3 atmosphere absolute (ATA)] hyperoxia (>= 95% O-2) for 6 h. Mice were either given simvastatin (20 mg center dot kg center dot(-1)center dot day(-1)) in saline or a saline vehicle for 3 days before oxygen exposure. Lung tissue, serum, and bronchoalveolar lavage fluid (BALF) were collected for analysis of proapoptotic proteins, low-density lipoprotein cholesterol (LDL-C) levels, and lung inflammation. Simvastatin treatment significantly reduced lung permeability, serum LDL-C levels, tissue apoptosis, and inflammation. However, simvastatin treatment had no effect on antioxidant enzyme activity, nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH4) expression, and Akt phosphorylation levels. Furthermore, we investigated the role of endothelial nitric oxide synthase (eNOS) in simvastatin protection through inhibiting eNOS activity with NG-nitro-Larginine methyl ester (L-NAME; 20 mg/kg). Results showed that the beneficial effects of simvastatin on ALI induced by HBO (anti-inflammatory, antiapoptotic, lipid lowering, and reduction in lung permeability) were reversed. These results showed that simvastatin curbs HBO-induced lung edema, permeability, inflammation, and apoptosis via upregulating eNOS expression and that simvastatin could be an effective therapy to treat prolonged HBO exposure.