Gazoni Leo M, Laubach Victor E, Mulloy Daniel P, Bellizzi A, Unger Eric B, Linden Joel, Ellman Peter I, Lisle Turner C, Kron Irving L
Department of Surgery, University of Virginia, Charlottesville 22908, USA.
J Thorac Cardiovasc Surg. 2008 Jan;135(1):156-65. doi: 10.1016/j.jtcvs.2007.08.041. Epub 2007 Nov 26.
Adenosine A2A 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 A2A 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.
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 degrees C). ATL-313 was administered 1 hour before ischemia intravenously, with the preservation solution, and/or during reperfusion.
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.
Adenosine A2A 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 A2A 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 A2A receptor antagonist, ZM 241385, supports that the mechanism of ATL-313 protection is specifically mediated via adenosine A2A receptor activation.
再灌注期间腺苷A2A受体激活可改善肺缺血-再灌注损伤。在本研究中，我们试图确定在移植前用强效且选择性的腺苷A2A受体激动剂ATL-313预处理兔，或者将ATL-313添加到保存液中，与在再灌注期间添加ATL-313相比，是否能产生等效或额外的保护作用。
使用离体、通气、体外血液灌注兔肺模型。所有组在18小时冷缺血（4℃）后进行2小时再灌注。ATL-313在缺血前1小时静脉给药、添加到保存液中及/或在再灌注期间给药。
用ATL-313预处理供体动物或仅在再灌注期间添加ATL-313均可改善肺功能，但当预处理与再灌注期间的治疗联合使用时，观察到的改善显著更大（所有P<.05）。联合治疗组中髓过氧化物酶水平、支气管肺泡灌洗肿瘤坏死因子α水平和肺水肿均最大程度降低。与ATL-313一起给予等摩尔量的强效且高度选择性的腺苷2A受体拮抗剂ZM 241385，导致ATL-313所赋予的保护作用丧失。
在缺血前和再灌注期间给予ATL-313激活腺苷A2A受体可对肺缺血-再灌注损伤产生最大程度的保护。腺苷A2A受体激活所观察到的肺功能改善与支气管肺泡灌洗肿瘤坏死因子α降低和肺髓过氧化物酶降低相关。同时给予腺苷A2A受体拮抗剂ZM 241385时观察到的保护作用丧失支持ATL-313的保护机制是通过腺苷A2A受体激活特异性介导的。
