Adenosine A1 receptor activation attenuates lung ischemia-reperfusion injury.
Adenosine A1 receptor activation attenuates lung ischemia-reperfusion injury.
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DOI：
10.1016/j.jtcvs.2013.01.006
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发表时间：
2013-06
影响因子：
6
通讯作者：
Laubach, Victor E.
中科院分区：
文献类型：
--
作者：
Fernandez, Lucas G.;Sharma, Ashish K.;LaPar, Damien J.;Kron, Irving L.;Laubach, Victor E.
缺血再灌注损伤是肺移植患者发病率和死亡率的重要因素。目前临床上没有治疗剂可用于预防缺血再灌注损伤，并且治疗策略限于维持氧合和肺功能。腺苷可通过与多种腺苷受体结合来调节炎症活动和损伤，但腺苷A1受体在缺血再灌注损伤和炎症中的作用尚不清楚。本研究验证了选择性外源性激活A1受体具有抗炎和减轻肺缺血-再灌注损伤的假设。野生型和A1受体敲除小鼠使用体内肺门钳夹模型进行1小时左肺缺血和2小时再灌注。A1受体激动剂CCPA在缺血前5分钟给药。再灌注后，通过测量气道阻力、肺顺应性和肺动脉压评价肺功能。使用湿/干重量比评估水肿。测定支气管肺泡灌洗液中的髓过氧化物酶和细胞因子水平，以确定中性粒细胞浸润和炎症。在野生型动物中，CCPA显着改善肺功能和衰减水肿，细胞因子的表达和髓过氧化物酶水平相比，溶剂处理的小鼠缺血再灌注后。A1受体敲除小鼠和野生型小鼠的肺缺血再灌注损伤相似，但CCPA对A1受体敲除小鼠无影响。体外用CCPA处理中性粒细胞显著降低趋化性。外源性A1受体活化改善肺功能，减少缺血再灌注后的炎症、水肿和中性粒细胞趋化性。这些结果表明，A1受体激动剂用于预防移植后肺缺血再灌注损伤的潜在治疗应用。
Ischemia-reperfusion injury significantly contributes to morbidity and mortality in lung transplant patients. Currently no therapeutic agents are clinically available to prevent ischemia-reperfusion injury, and treatment strategies are limited to maintaining oxygenation and lung function. Adenosine can modulate inflammatory activity and injury via binding to various adenosine receptors, but the role of adenosine A1 receptor in ischemia-reperfusion injury and inflammation is not well understood. This study tests the hypothesis that selective, exogenous activation of A1 receptor is anti-inflammatory and attenuates lung ischemia-reperfusion injury. Wild-type and A1 receptor knockout mice underwent 1 hour left lung ischemia and 2 hours reperfusion using an in vivo hilar-clamp model. An A1 receptor agonist, CCPA, was administered 5 minutes before ischemia. After reperfusion, lung function was evaluated by measuring airway resistance, pulmonary compliance and pulmonary artery pressure. Wet/dry weight ratio was used to assess edema. Myeloperoxidase and cytokine levels in bronchoalveolar lavage fluid were measured to determine neutrophil infiltration and inflammation. In wild-type animals, CCPA significantly improved lung function and attenuated edema, cytokine expression and myeloperoxidase levels compared to vehicle-treated mice after ischemia-reperfusion. Lung ischemia-reperfusion injury was similar between A1 receptor knockout and wild-type mice, but CCPA had no effects in A1 receptor knockout mice. In vitro treatment of neutrophils with CCPA significantly reduced chemotaxis. Exogenous A1 receptor activation improves lung function and decreases inflammation, edema and neutrophil chemotaxis after ischemia-reperfusion. These results suggest a potential therapeutic application for A1 receptor agonists for the prevention of lung ischemia-reperfusion injury after transplantation.
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DOI：
10.1073/pnas.171317998
发表时间：
2001-08-14
影响因子：
11.1
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发表时间：
2011-05-01
影响因子：
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