Additive protection against lung ischemia-reperfusion injury by adenosine A2A receptor activation before procurement and during reperfusion
Additive protection against lung ischemia-reperfusion injury by adenosine A2A receptor activation before procurement and during reperfusion
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DOI：
10.1016/j.jtcvs.2007.08.041
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发表时间：
2008-01-01
影响因子：
6
通讯作者：
Kron, Irving L.
中科院分区：
文献类型：
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作者：
Gazoni, Leo M.;Laubach, Victor E.;Kron, Irving L.
目的：再灌注时腺苷A（2A）受体的激活可改善肺缺血再灌注损伤。在这项研究中，我们试图确定在移植前用强效和选择性的腺苷a （2A）受体激动剂ATL-313对家兔进行预处理，或者在保存液中加入ATL-313是否与在再灌注时加入ATL-313相比，能产生同等或额外的保护作用。方法：采用离体、通气、离体血灌注兔肺模型。各组在冷缺血18小时（4℃）后进行2小时再灌注。ATL-313在缺血前1小时静脉给予，与保存液一起给予，和/或在再灌注时给予。结果：供体动物经ATL-313预处理或仅在再灌注时添加ATL-313均可改善肺功能，但经预处理与再灌注时联合治疗时肺功能改善更明显（P < 0.05）。联合治疗组髓过氧化物酶水平、支气管肺泡灌洗肿瘤坏死因子α水平、肺水肿均显著降低。等量的强效和高选择性腺苷2A受体拮抗剂ZM 241385与ATL-313一起施用，导致ATL-313所赋予的保护丧失。结论：ATL-313激活腺苷A（2A）受体在缺血前和再灌注时对肺缺血-再灌注损伤的保护作用最大。腺苷A（2A）受体激活后肺功能改善与支气管肺泡灌洗肿瘤坏死因子α和肺髓过氧化物酶降低相关。同时给予腺苷A（2A）受体拮抗剂ZM 241385观察到保护丧失，支持ATL-313的保护机制是通过腺苷A（2A）受体激活特异性介导的。
Objective: Adenosine A(2A) receptor activation during reperfusion improves lung ischemia- reperfusion injury. In this study we sought to determine whether pretreatment of rabbits with a potent and selective adenosine A(2A) receptor agonist, ATL-313, before transplantation or whether adding ATL-313 to the preservation solution results in equivalent or additional protection compared with ATL-313 added during reperfusion.Methods: An isolated, ventilated, ex vivo blood-perfused rabbit lung model was used. All groups underwent 2 hours of reperfusion after 18 hours of cold ischemia (4 C). ATL-313 was administered 1 hour before ischemia intravenously, with the preservation solution, and/or during reperfusion.Results: Both pretreatment of donor animals with ATL-313 or adding ATL-313 just during reperfusion improved pulmonary function, but significantly greater improvement was observed when pretreatment and treatment during reperfusion were combined (all P < .05). Myeloperoxidase levels, bronchoalveolar lavage tumor necrosis factor alpha levels, and pulmonary edema were all maximally decreased in the combined treatment group. The administration of an equimolar amount of the potent and highly selective adenosine 2A receptor antagonist, ZM 241385, along with ATL-313, resulted in the loss of protection conferred by ATL-313.Conclusions: Adenosine A(2A) receptor activation with ATL-313 results in the greatest protection against lung ischemia- reperfusion injury when given before ischemia and during reperfusion. Improved pulmonary function observed with adenosine A(2A) receptor activation was correlated with decreased bronchoalveolar lavage tumor necrosis factor alpha and decreased lung myeloperoxidase. The loss of protection observed with the concurrent administration of the adenosine A(2A) receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A(2A) receptor activation.