Naidu Babu V, Woolley Steven M, Farivar Alexander S, Thomas Robert, Fraga Charles, Mulligan Michael S
Division of Cardiothoracic Surgery, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, USA.
J Thorac Cardiovasc Surg. 2003 Aug;126(2):482-9. doi: 10.1016/s0022-5223(03)00699-8.
Statins are lipid-lowering drugs with anti-inflammatory and antioxidant properties. This study explores the potential of these commonly prescribed agents to ameliorate lung ischemia-reperfusion injury.
Left lungs of Long-Evans rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received simvastatin orally (0.5 mg/kg) for 5 days before the experiment. Injury was quantitated in terms of tissue myeloperoxidase content, vascular permeability ((125)I bovine serum albumin extravasation), and bronchoalveolar lavage leukocyte and cytokine content. Changes in nuclear translocation of transcription factors were evaluated by electromobility shift assay. Additional animals received N(G)-nitro-L-arginine methyl ester before ischemia-reperfusion to assess whether inhibition of nitric oxide synthase could reverse simvastatin's protective effects. The presence of nicotinamide adenine dinucleotide phosphate oxidase was also evaluated using enzyme staining both histologically and in native electrophoresis.
Lung vascular permeability was reduced in treated animals by 71% compared with positive controls (P <.001). Administration of N(G)-nitro-L-arginine methyl ester reversed this protection. The protective effects of statin pretreatment correlated with a 68% reduction in tissue myeloperoxidase content (P <.01), marked reductions in bronchoalveolar lavage leukocyte accumulation, and decreased expression of proinflammatory cytokines. Nicotinamide adenine dinucleotide phosphate oxidase expression also decreased with statin treatment.
In addition to its antioxidant properties, the protective effects of simvastatin are likely mediated by modulation of endothelial nitric oxide synthase. The potential to pretreat recipients of lung transplantation with statins to ameliorate reperfusion injury is promising.
他汀类药物是具有抗炎和抗氧化特性的降脂药物。本研究探讨这些常用药物改善肺缺血再灌注损伤的潜力。
将Long-Evans大鼠的左肺缺血90分钟，再灌注长达4小时。治疗组动物在实验前5天口服辛伐他汀（0.5毫克/千克）。通过组织髓过氧化物酶含量、血管通透性（（125）I牛血清白蛋白外渗）以及支气管肺泡灌洗白细胞和细胞因子含量来定量损伤。通过电泳迁移率变动分析评估转录因子核转位的变化。另外的动物在缺血再灌注前接受N（G）-硝基-L-精氨酸甲酯，以评估一氧化氮合酶的抑制是否能逆转辛伐他汀的保护作用。还使用组织学酶染色和天然电泳评估烟酰胺腺嘌呤二核苷酸磷酸氧化酶的存在情况。
与阳性对照组相比，治疗组动物的肺血管通透性降低了71%（P<.001）。给予N（G）-硝基-L-精氨酸甲酯可逆转这种保护作用。他汀类药物预处理的保护作用与组织髓过氧化物酶含量降低68%（P<.01）、支气管肺泡灌洗白细胞积聚显著减少以及促炎细胞因子表达降低相关。他汀类药物治疗后烟酰胺腺嘌呤二核苷酸磷酸氧化酶表达也降低。
除了其抗氧化特性外，辛伐他汀的保护作用可能是通过调节内皮型一氧化氮合酶介导的。用他汀类药物预处理肺移植受者以改善再灌注损伤的潜力很有前景。
