辛伐他汀预先给药对大鼠肢体缺血再灌注时肺损伤的影响

Effects of simvastatin pretreatment on Iung injury induced by ischemia-reperfusion of hind limbs in rats

目的探讨辛伐他汀预先给药对大鼠肢体缺血再灌注时肺损伤的影响。方法雄性SD大鼠40只,体重250～300g,随机分为5组（n=8）,假手术组（S组）、肢体缺血再灌注组（IR组）分别给予等容量（1ml）的蒸馏水,辛伐他汀1、5、10mg·kg^-1·d^-1组（S1组、S5组、S10组）分别于每日清晨将1、5、10mg·kg^-1·d^-1辛伐他汀溶于1ml蒸馏水灌胃1次,连续3d,IR组、S1组、S5组和S10组于最后一次给药后2h行双后肢缺血再灌注。再灌注3h时取肺组织,进行病理学观察,并测定肺组织含水率、髓过氧化物酶（MPO）、一氧化氮合酶（NOS）活性、一氧化氮（NO）和丙二醛（MDA）含量、内皮细胞型NOS（eNOS）和诱导型NOS（iNOS）蛋白表达。结果IR组肺组织病理损伤较重,S1组、S5组、S10组肺组织病理损伤减轻,S10组接近于正常肺组织。与S组比较,IR组、S1组和S5组肺组织含水率、MDA含量、MPO活性、NOS活性、NO含量升高,eNOS蛋白表达下调,iNOS蛋白表达上调,S10组NOS活性及NO含量升高,iNOS蛋白表达上调（P〈0.01）;与IR组比较,S1组、S5组和S10组肺组织含水率、MDA含量及MPO活性降低,NOS活性及NO含量升高,eNOS蛋白表达上调,iNOS蛋白表达下调,呈剂量依赖性（P〈0.05或0.01）。结论辛伐他汀1、5、10mg·kg^-1·d^-1（连续3d）预先给药对肢体缺血再灌注大鼠肺组织产生一定的保护作用,且呈剂量依赖性,其机制可能与减轻肺组织炎性反应及氧化损伤,提高NO生成有关。

Objective To investigate the effects of simvastatin pretreatment on lung injury induced by ischemia-reperfusion （I/R） of hind limbs in rats. Methods Forty male SD rats weighing 250-300 g were randomly divided into5 groups （n = 8 each）： group Ⅰ sham operation （S）; group Ⅱ I/R; group Ⅲ, Ⅳ, Ⅴreceived simvastatin 1, 5, 10 mg·kg^-1·d^-1 respectively via an oro-gastric tube for 3 days before I/R （S1 , S5 , S10） . I/R of hind limbs was produced by occlusion of bilateral femoral arteries for 2 h followed by 3 h reperfusion. The animals were killed at the end of 3 h reperfusion and their lungs were immediately removed for determination of the lung watcr, malondialdchyde （MDA） and NO content and mycloperoxidase （MPO） and nitric oxide synthase （NOS） activities. The lungs were also assessed for protein expression of endothelial nitric oxide synthase （eNOS） and inducible nitric oxide synthase （iNOS） using Western blot analysis. Results （1） Alveolar edema, localized atelectasis and large amount of polymorphonuclear （PMN） infiltration were found in I/R group and were ameliorated in the 3 simvastatin groups （S1, S5, S10） in a dose-dependent manner. （2） Lung water, MDA content and MPO activity were significantly increased in I/R group as compared with sham operation group （S）. The I/R-induced increase in lung water, MDA content and MPO activity were significantly attenuated in S10 group. （3） NOS activity and NO content were significantly higher in the 3 simvastatin groups than in group S and I/R. The I/R-induced decrease in eNOS protein expression and increase in iNOS protein expression were significantly attenuated by simvastatin pretreatment in a dose-dependent manner. Conclusion Simvastatin pretreatment has protective effects against lung injury induced by I/R of the hind limbs in a dose-dependent manner by reduction of inflammatory reaction and oxidative damage in the lungs.