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诱生型一氧化氮合酶在肺移植大鼠肺血管功能改变中的作用
The inducible nitric oxide synthase involved in the pulmonary vascular dysfunction in a rat model of lung transplantation

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DOI:
作者:
吴镜湘，朱宏伟，徐美英
WU Jingxiang , ZHU Hongwei , Xu Meiying
作者单位:
上海交通大学附属胸科医院麻醉科
Department of Anesthesiology Shanghai Chest Hospital，Shanghai Jiaotong University
关键词:
肺移植；缺血再灌注损伤；内皮功能；离体肺动脉；一氧化氮合酶
Lung transplantation ;Ischemia-reperfusion injury; Endothelial function; isolated pulmonary artery; nitric oxide synthase
摘要:
目的 观察肺移植大鼠再灌注早期肺血管功能的改变，探讨诱生型一氧化氮合成酶在肺移植大鼠肺血管功能改变中的作用。方法 雄性SD大鼠40只，体重300g～400g，先取15只作为移植供体鼠，余下大鼠分为2组：对照组（n=10），仅做左侧开关胸处理；移植组（n=15），即肺移植受体组，采用改良三袖套法建立大鼠左肺原位移植模型，肺移植完成，再灌注2h后处死大鼠，取左肺组织检测毛细血管通透性指标肺湿干比(W/D)﹑肺内伊文思兰含量；测试氧化应激指标丙二醛(MDA)和髓过氧化物酶(MPO)含量；同时检测诱生型一氧化氮合酶(iNOS)、内皮源性一氧化氮合酶(eNOS)含量的变化。另外取大鼠肺动脉，制备离体肺动脉环，再细分为内皮完整组和去内皮化组，采用乙酰胆碱的累积舒张反应曲线法测试血管环舒张功能改变，采用去氧肾上腺素的累积收缩反应曲线法测试收血管环缩功能的改变；并采用非选择性NOS抑制剂(L-NAME，300 μM) 和选择性 iNOS抑制剂（L-NIL，10μM）孵育血管20min，比较其对离体肺动脉血管环收缩和舒张功能的影响。结果 移植组的W/D和肺内伊文思兰含量高于对照组(P<0.05)；MDA、MPO增高；肺内iNOS活性高于于对照组(P<0.05)，eNOS活性低于对照组(P<0.05)；移植组离体肺动脉舒张功能下降（P<0.05），而L-NIL（10μM）预处理后血管舒张效应恢复到对照组水平；移植组离体肺动脉的收缩功能下降（P<0.05），去内皮化对移植组肺动脉收缩功能无显著影响，采用L-NAME或L-NIL预处理后移植组血管收缩功能明显恢复（P<0.05）。结论 移植肺再灌注早期一方面氧化应激损伤加重，肺毛细血管通透性增加，另一方面肺动脉的收缩和舒张功能都有不同程度的损害，其中舒张功能的损害可能与内皮功能相关，而收缩功能的损害主要与平滑肌功能相关，移植肺再灌注早期的这两方面改变其机制可能与肺内iNOS活性的异常增加以及eNOS活性的降低有关。
Objective To determine the contribution of inducible nitric oxide synthase (iNOS) in pulmonary vascular dysfunction on early ischemia-reperfusion injury in rats lung transplantation. Methods Fourty Sprague-Dawley rats weighing 300g~400g were allocated into two groups after : One was control (sham， n=10，) group,only thoractomy and ventilation were done. The other was lung transplant group（n=15,rate of donor to recipient was 1:1, actually these fifteen rats were recipients ）. The model of rat orthotopic left lung allograft transplantation was established by using the cuffs technique. After the transplantation a two-hour reperfusion was followed. The lungs were harvested and wet-to-dry lung weight ratio (W/D), lung Evans blue contents, levels of myeloperoxidase (MPO), malondialdehyde (MDA) and activity of inducible nitric oxide synthase(iNOS) and endothelial NOS (eNOS) were detected by biochemical methods. Isolated pulmonary artery rings were prepared. Ring responses were evaluated in the presence and absence of endothelium and non-selective NOS inhibitor (L-NAME, 300μM) or selective iNOS inhibitor (L-NIL,10μM) incubation. Either vascular relaxation function or contraction functionin were tested. Results The lung wet／dry ratio and Evans blue contents in lung transplant group were higher than those in control group; the level of MDA and MPO and iNOS activity in lung transplant group were higher than those of control group, but the eNOS activity was lower. When compared with the control group, both relaxation and constriction function of the isolated pulmonary artery rings were impaired in the lung transplant group. But when pretreated with selective iNOS inhibitor( L-NIL ,10μM),relaxation function can be restored. Both groups produced a concentration-dependent contractile responses to phenylephrine. In the lung transplant group, the contractile function of pulmonary artery with or without endothelium showed no difference (P>0.05). While the contractile function of the lung transplant group can be restored by pretreating with L-NAME or L-NIL. Conclusions The pulmonary capillary permeability increases during reperfusion after lung transplantation. Both diastolic and contractile function of isolated pulmonary artery have been damaged after lung transplatation. The damagment of diastolic function is related to endothelial dysfunction, while the contractile function may be related to the impairment of smooth muscle function. The abnormally increased iNOS may be responsible for the pulmonary vascular dysfunction in rats lung transplantation

 

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