肾上腺髓质素对高肺血流大鼠肺组织氧化应激的调节作用

摘要

目的: 研究肾上腺髓质素(ADM)对高肺血流性肺动脉高压大鼠肺组织氧化应激的调节作用及其机制.方法: 健康雄性SD大鼠随机分为对照组、分流组和分流+ADM组.对后2组大鼠行腹主动脉-下腔静脉分流术.8周后,对分流+ADM组大鼠皮下埋微量渗透泵持续予ADM 1.5 μg·kg-1·h-1.继续饲养2周后,右心导管法测定平均肺动脉压(mPAP)和右心室/(左心室+室间隔)重量比值,检测肺中、小肌型动脉相对中膜厚度(RMT),比色法测定肺组织匀浆丙二醛(MDA)含量、总抗氧化能力(T-AOC)、超氧化物歧化酶(SOD)活性和谷胱甘肽过氧化物酶(GSH-Px)活性,Western blot法检测肺组织还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶4(NOX4)的表达.结果: 与对照组相比,分流组大鼠的mPAP、右心室肥厚程度以及肺中、小肌型动脉RMT均明显增加,肺组织MDA 含量明显升高,T-AOC、SOD活性和GSH-Px活性均明显降低,肺组织NOX4表达明显升高.ADM使肺动脉压力明显回降,右心室肥厚程度减轻,肺血管结构改变缓解,肺组织MDA 含量明显下降,T-AOC、SOD活性和GSH-Px活性明显升高,肺组织NOX4表达明显降低.结论: ADM能够抑制大鼠高肺血流性肺动脉高压和肺血管结构重构形成中的氧化应激反应,作用机制可能与其下调肺组织NOX4表达以及增强抗氧化活性有关.%AIM: To explore the regulatory effect of adrenomedullin (ADM) on pulmonary oxidative stress in the rats with pulmonary hypertension induced by high blood flow.METHODS: Healthy male SD rats (n=22) were randomly divided into control group, shunt group and shunt with ADM group.Abdominal aorta and inferior vena cava shunting was produced in the rats in shunt group and shunt with ADM group.After 8 weeks, ADM (1.5 μg·kg-1·h-1) was administered into the rats in shunt with ADM group subcutaneously by mini-osmotic pump for 2 weeks.Mean pulmonary artery pressure (mPAP) was evaluated by a right cardiac catheterization procedure.The ratio of right ventricular mass to left ventricular plus interventricular septal mass [RV/(LV+SP)] and relative medial thickness (RMT) in pulmonary muscularized arteries were calculated.The content of malonaldehyde (MDA), total antioxidative capacity (T-AOC), and activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissues were detected by colorimetry.The expression of NADPH oxidase 4 (NOX4) in the lung tissue was analyzed by Western blot.RESULTS: Compared with control group, the mPAP, RV/(LV+SP) and RMT in pulmonary muscularized arteries in shunt group were all significantly increased.The content of MDA and the expression of NOX4 in the lung tissues were significantly increased.The T-AOC, and activity of SOD and GSH-Px in the lung tissues were significantly decreased.However, mPAP, RV/(LV+SP) and RMT in pulmonary muscularized arteries in shunt with ADM group were significantly decreased as compared with shunt group.Meanwhile, ADM decreased the content of MDA and the expression of NOX4 in the lung tissues, but increased the T-AOC, and activity of SOD and GSH-Px in the lung tissue of shunt rats.CONCLUSION: ADM inhibits oxidative stress response in the development of pulmonary hypertension and pulmonary vascular structural remodeling induced by high pulmonary blood flow in the rats by down-regulating the NOX4 expression and strengthening the anti-oxidation response.