依达拉奉对大鼠肺移植缺血再灌注损伤保护作用的实验研究
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摘要
目的:探讨依达拉奉对大鼠单肺移植中供体肺缺血再灌注损伤的保护作用及其可能的作用机制。
方法:将20对SD大鼠随机分为对照组(LPD液组)和实验组(依达拉奉组)两组,每组10对。对照组应用低钾右旋糖苷液行肺灌洗及肺保存,实验组用含依达拉奉20mg/L的LPD液行肺灌洗及肺保存。采用改进的三袖套吻合技术建立大鼠左肺原位移植缺血再灌注损伤模型,行大鼠左肺原位移植手术。肺移植术后30、60、90min时做血气分析;90分钟处死受体后获取移植的左肺,并行移植肺湿干比(W/D)、丙二醛(MDA)、及髓过氧化物酶(MPO)、超氧化物歧化酶(SOD)的检测。光镜下观察左侧供肺组织结构的病理变化。
结果:
(1)成功的建立了大鼠左肺原位移植缺血再灌注损伤模型。
(2)血气分析:随着移植后时间的延长,两组PaO2均有所降低,实验组PaO2于移植后30、60、90min(118.00±23.62,79.70±13.21,68.43±8.41mmHg)显著高于对照组(99.41±5.97,68.20±13.24,55.27±7.83mmHg)(P<0.05);随着移植后时间的延长,两组PaCO2均有所上升,实验组PaCO2于移植后30、60、90min(36.42±6.25,40.02±2.89,56.92±3.94 mmHg)显著低于对照组(48.56±8.32,53.55±6.12,71.07±9.48 mmHg)(P<0.05)。
(3)肺组织湿/干重比:实验组的W/D比值为4.93±0.26;对照组W/D比值为5.86±0.46两组间差异有统计学意义(P<0.05)。
(4)氧自由基指标:实验组MDA较对照组降低,其差异有统计学意义(P<0.01);实验组SOD较LPD液组升高,其差异有统计学意义(P<0.01)。
(5)炎症指标:实验组MPO较对照组降低,其差异有统计学意义(P<0.01)。病理变化:光镜下观察见肺泡结构破坏,肺泡细胞肿胀,肺泡间质水肿增厚,炎性细胞及中性粒细胞浸润。实验组在组织充血、渗出及炎性细胞浸润情况均较对照组好转。
结论:依达拉奉可减轻供体肺的缺血再灌注损伤,改善移植肺功能,对移植肺缺血再灌注损伤具有一定的保护作用,其作用机制可能与清除氧自由基,抑制脂质过氧化有关。
Objective: To investigate the protective effects of edaravone on ischemia-reperfusion during rats lung-transplant,and explore the possible mechanism.
Methods: The 20 couples of SD rats were divided into two groups LPD group and Edaravone group randomly,10 in each group. All rats in experiment group were operated for left orthotopic lung allograft transplantation by using non-vessel endothelium cuff technique. All rats in Edaravone group were operated for left orthotopic lung allograft transplantation by using vessel endothelium cuff technique. When the left lung had been transplanted, systemic PaO2 and PaCO2 were determined in blood samples from ilium artery and blood. supply of the transplanted lung tissue was observed.And the protective effects was assessed by measuring the levels of the malondialdehyde (MDA), myeloperoxidase (MPO),superoxide dismutase(SOD) and. wet-to-dty weight ratio compared in the lung tissues.Histopathological changes and the ultrastructural assessment of pulmonary were examined.
Results:
(1)Set up a single lung in site ischemia-referfusion model in rat.
(2)All animals of groups A and B survived the entire observation period.The PaO2 decreased significantly after translantation in all groups. The E group showed significantly higher levels of PaO2 at the 30 th,60 th and 90 th minutes of translantation (118.00±23.62,79.70±13.21,68.43±8.41 mmHg) in comparison to LPD group(P<0.05); The PaCO2 increased significantly after translantation in all groups. The E group showed significantly lower levels of PaCO2 at the 15th,60 th and 90 th minutes of translantation (36.42±6.25, 40.02±2.89,56.92±3.94 mmHg) in comparison to LPD group (P<0.05).
(3)The levers of W/D,MDA content and MPO activity(P<0.01) were significantly decreased in E group than LPD group.But the avtivity of SOD was significantly higher in LPD group than E group.
(4)Pulmonary H-P stain showed edema (both interstitial and alveolarspace) and neutrophil infiltration in alveolar tissue and damage of lveolus after transplantation. In the process of ischemia-reperfusion the lung injury was aggravating progressively in the LPD group.
Conclusion: A free radical scavenger,edaravone,has a protective effect on pulmonary ischemia-reperfusion injury in rat single lung transplantation model.The mechanism may be related with suppressing oxidative damage and phospholipase A2 activation.
方法:将20对SD大鼠随机分为对照组(LPD液组)和实验组(依达拉奉组)两组,每组10对。对照组应用低钾右旋糖苷液行肺灌洗及肺保存,实验组用含依达拉奉20mg/L的LPD液行肺灌洗及肺保存。采用改进的三袖套吻合技术建立大鼠左肺原位移植缺血再灌注损伤模型,行大鼠左肺原位移植手术。肺移植术后30、60、90min时做血气分析;90分钟处死受体后获取移植的左肺,并行移植肺湿干比(W/D)、丙二醛(MDA)、及髓过氧化物酶(MPO)、超氧化物歧化酶(SOD)的检测。光镜下观察左侧供肺组织结构的病理变化。
结果:
(1)成功的建立了大鼠左肺原位移植缺血再灌注损伤模型。
(2)血气分析:随着移植后时间的延长,两组PaO2均有所降低,实验组PaO2于移植后30、60、90min(118.00±23.62,79.70±13.21,68.43±8.41mmHg)显著高于对照组(99.41±5.97,68.20±13.24,55.27±7.83mmHg)(P<0.05);随着移植后时间的延长,两组PaCO2均有所上升,实验组PaCO2于移植后30、60、90min(36.42±6.25,40.02±2.89,56.92±3.94 mmHg)显著低于对照组(48.56±8.32,53.55±6.12,71.07±9.48 mmHg)(P<0.05)。
(3)肺组织湿/干重比:实验组的W/D比值为4.93±0.26;对照组W/D比值为5.86±0.46两组间差异有统计学意义(P<0.05)。
(4)氧自由基指标:实验组MDA较对照组降低,其差异有统计学意义(P<0.01);实验组SOD较LPD液组升高,其差异有统计学意义(P<0.01)。
(5)炎症指标:实验组MPO较对照组降低,其差异有统计学意义(P<0.01)。病理变化:光镜下观察见肺泡结构破坏,肺泡细胞肿胀,肺泡间质水肿增厚,炎性细胞及中性粒细胞浸润。实验组在组织充血、渗出及炎性细胞浸润情况均较对照组好转。
结论:依达拉奉可减轻供体肺的缺血再灌注损伤,改善移植肺功能,对移植肺缺血再灌注损伤具有一定的保护作用,其作用机制可能与清除氧自由基,抑制脂质过氧化有关。
Objective: To investigate the protective effects of edaravone on ischemia-reperfusion during rats lung-transplant,and explore the possible mechanism.
Methods: The 20 couples of SD rats were divided into two groups LPD group and Edaravone group randomly,10 in each group. All rats in experiment group were operated for left orthotopic lung allograft transplantation by using non-vessel endothelium cuff technique. All rats in Edaravone group were operated for left orthotopic lung allograft transplantation by using vessel endothelium cuff technique. When the left lung had been transplanted, systemic PaO2 and PaCO2 were determined in blood samples from ilium artery and blood. supply of the transplanted lung tissue was observed.And the protective effects was assessed by measuring the levels of the malondialdehyde (MDA), myeloperoxidase (MPO),superoxide dismutase(SOD) and. wet-to-dty weight ratio compared in the lung tissues.Histopathological changes and the ultrastructural assessment of pulmonary were examined.
Results:
(1)Set up a single lung in site ischemia-referfusion model in rat.
(2)All animals of groups A and B survived the entire observation period.The PaO2 decreased significantly after translantation in all groups. The E group showed significantly higher levels of PaO2 at the 30 th,60 th and 90 th minutes of translantation (118.00±23.62,79.70±13.21,68.43±8.41 mmHg) in comparison to LPD group(P<0.05); The PaCO2 increased significantly after translantation in all groups. The E group showed significantly lower levels of PaCO2 at the 15th,60 th and 90 th minutes of translantation (36.42±6.25, 40.02±2.89,56.92±3.94 mmHg) in comparison to LPD group (P<0.05).
(3)The levers of W/D,MDA content and MPO activity(P<0.01) were significantly decreased in E group than LPD group.But the avtivity of SOD was significantly higher in LPD group than E group.
(4)Pulmonary H-P stain showed edema (both interstitial and alveolarspace) and neutrophil infiltration in alveolar tissue and damage of lveolus after transplantation. In the process of ischemia-reperfusion the lung injury was aggravating progressively in the LPD group.
Conclusion: A free radical scavenger,edaravone,has a protective effect on pulmonary ischemia-reperfusion injury in rat single lung transplantation model.The mechanism may be related with suppressing oxidative damage and phospholipase A2 activation.
引文
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44. Shiraishi T, Igisu H, Shirakusa T. Effects of pH and temperature on lung preservation:a study with an isolated rat lung reperfusion model.:Ann Thorac Surg. 1994;57 (3):639-43.
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32. Yamashita M, Schmid RA, Ando K, et al. Nitroprusside ameliorates lung allograft reperfusion injury. Ann Thorac Surg, 1996, 62:791-796.
33. Lockinger A, Schutte H, Walmrath D, et al.Protection against gas exchange abn -ormalities by pre-aerosolized PGE1, iloprost and nitroprusside in lung ischemia-reperfusion. Transplantation, 2001 71: 185-193.
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35. Kawashima M, Bando T, Nakamura T, et al.Cytoprotective effects of nitroglycerin in ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med, 2000, 16 1:935-943.
36. Kayano K, Toda K, Naka Y, et al.Superior protection in orthotopic rat lung trans -plantation with cyclic adenosine monophosphate and nitroglycerin-containing preservation solution. J Thorac Cardiovasc Surg, 1999, 118:135-144.
37. Naka Y, Chowdhury NC,Liao H, et al. Enhanced preservation of orthotopically transplanted rat lungs by nitroglycerin but not hydralazine:requirement for graft vascular homeostasis beyond harvest vasodilation Circ Res, 1995, 76:900-906.
38. Henneberg SW.Inhalation of nitric oxide as a treament of pulmonary hypertension in congential diaphragmatic hernia.J Pediat Surg, 1995, 30:853-855.
39. Wessel DL Use of inhaled nitric oxide and acetycholine in the evaluation function after ardiopulmonary bypass .Circulation,1993, 88:2128-2138.
40. Wessel DL, Sandler D ,et al.Use of inhaled nitric oxide in the evaluation function after ardiopulmonary bypass . Transplantation.,1993, 12:1024-10398.
41. Veldhuizen RAW, LEEJ, Sandler D, et al.Alterations in pulmonary surfactant com -position and activity after experimental lung transplantation. Am Respir Dis 1993;148 :208 -15.
42. Strttber M, Hogl fekd JM, Fraund S, et al .Low-potassium dextran solution ameliorates reperfusion injury of the lung and protects surfactant Function. J Thorac Cardiovasc Surg.,2000;120:566-72.
43. Muller C, Hoffmann H, Bittmann I, et al. Hypothermic storage alone in lung preservation for transplantation:a metabolic, light microscopic, and functional analysis after 8 hours of preservation.Transplantation.,1997 15(5):625-30.
44. Shiraishi T, Igisu H, Shirakusa T. Effects of pH and temperature on lung preservation:a study with an isolated rat lung reperfusion model.:Ann Thorac Surg. 1994;57 (3):639-43.
45. Kelly RF,Murar J,Hong Z,et a1.Low potassium dextran lung preservation solution reduces reactive oxygen species production.Ann Thorac Surg,2003,75:1705-1710.
46. Wittwer T,Franke UF,Fehreubach A,et a1.Experimental lungtran splantation:impact of preservation solution and route of deliver.J Heart Lung Transplant,2005,24:1081-1090.
47.张国报,乔晨晖,曹劝省,等.肺动脉和支气管动脉双循环冲洗在供肺保存中的作用.郑州大学学报,2005,40:868-870。
48. Serrick CJ,Jomjoum A,Resl A,et a1.Amelioration of pulmonary allograft injury by administrating a second rising solution.Thorac Cardiovasc Surg,1996,1 124:1010.
49. Sakuma T,Tsukano C,Ishigaki M,et a1.Lung deflation impairs alveolar epithelial fluid transport in ischemic rab bit and rat lun gs.Transplantation,2000,69:1785-1793.
50.杨秀滨,吴清玉,刘小燕,等.肺泡内不同氧浓度对供肺保存效果的影响.中华器官移植杂志,2001,22:264-265.