Protection from pulmonary ischemia-reperfusion injury by adenosine A2A receptor activation.
Protection from pulmonary ischemia-reperfusion injury by adenosine A2A receptor activation.
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DOI：
10.1186/1465-9921-10-58
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发表时间：
2009-06-26
影响因子：
5.8
通讯作者：
Laubach VE
中科院分区：
文献类型：
--
作者：
Sharma AK;Linden J;Kron IL;Laubach VE
肺缺血再灌注损伤是肺移植术后的主要障碍之一，其发病率和死亡率均较高。然而，肺细胞群的各种亚群在肺IR损伤的发病机制中的作用和细胞保护机制仍有待阐明。在本研究中，我们研究了腺苷A2 A受体（A2 AAR）激活对居民肺细胞IR损伤后，使用一个孤立的，缓冲液灌注的小鼠肺模型。为了评估A2 AAR激活的保护作用，研究了三组C57 BL/6 J小鼠：假手术组（灌注2小时，无缺血）、IR组（缺血1小时+再灌注1小时）和IR+ ATL 313组，其中ATL 313，一种特异性A2 AAR激动剂，在缺血后被包括在再灌注缓冲液中。还在A2 AAR敲除小鼠中IR损伤后进行肺损伤参数和肺功能研究，有或没有ATL 313预处理。使用缓冲液灌注的离体肺系统评估肺功能。通过评估肺水肿、血管通透性、细胞因子/趋化因子活化和支气管肺泡液中的髓过氧化物酶水平来测量肺损伤。IR后，来自C57 BL/6 J野生型小鼠的肺显示出显著的功能障碍（气道阻力增加、肺动脉压和肺顺应性降低）和显著的损伤（血管通透性增加和水肿）。IR后的肺损伤和功能障碍通过ATL 313治疗显著减轻。IR后TNF-α、KC（CXCL 1）、MIP-2（CXCL 2）和RANTES（CCL 5）的显著诱导也被ATL 313处理减弱。来自A2 AAR敲除小鼠的肺在IR后也显示出显著的功能障碍、损伤和细胞因子/趋化因子产生，但ATL 313在这些小鼠中没有作用。A2 AAR的特异性活化通过减轻炎症提供了针对肺IR损伤的有效保护。这种保护作用在没有循环血液的情况下发生，从而表明A2 AAR活化对驻留肺细胞如肺泡巨噬细胞的保护作用。特异性A2 AAR激活可能是预防或治疗移植患者肺移植物功能障碍的有希望的治疗靶点。
Lung ischemia-reperfusion (IR) injury leads to significant morbidity and mortality which remains a major obstacle after lung transplantation. However, the role of various subset(s) of lung cell populations in the pathogenesis of lung IR injury and the mechanisms of cellular protection remain to be elucidated. In the present study, we investigated the effects of adenosine A2A receptor (A2AAR) activation on resident lung cells after IR injury using an isolated, buffer-perfused murine lung model. To assess the protective effects of A2AAR activation, three groups of C57BL/6J mice were studied: a sham group (perfused for 2 hr with no ischemia), an IR group (1 hr ischemia + 1 hr reperfusion) and an IR+ATL313 group where ATL313, a specific A2AAR agonist, was included in the reperfusion buffer after ischemia. Lung injury parameters and pulmonary function studies were also performed after IR injury in A2AAR knockout mice, with or without ATL313 pretreatment. Lung function was assessed using a buffer-perfused isolated lung system. Lung injury was measured by assessing lung edema, vascular permeability, cytokine/chemokine activation and myeloperoxidase levels in the bronchoalveolar fluid. After IR, lungs from C57BL/6J wild-type mice displayed significant dysfunction (increased airway resistance, pulmonary artery pressure and decreased pulmonary compliance) and significant injury (increased vascular permeability and edema). Lung injury and dysfunction after IR were significantly attenuated by ATL313 treatment. Significant induction of TNF-α, KC (CXCL1), MIP-2 (CXCL2) and RANTES (CCL5) occurred after IR which was also attenuated by ATL313 treatment. Lungs from A2AAR knockout mice also displayed significant dysfunction, injury and cytokine/chemokine production after IR, but ATL313 had no effect in these mice. Specific activation of A2AARs provides potent protection against lung IR injury via attenuation of inflammation. This protection occurs in the absence of circulating blood thereby indicating a protective role of A2AAR activation on resident lung cells such as alveolar macrophages. Specific A2AAR activation may be a promising therapeutic target for the prevention or treatment of pulmonary graft dysfunction in transplant patients.
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DOI：
10.1016/j.jtcvs.2007.08.041
发表时间：
2008-01-01
影响因子：
6
作者：
Gazoni, Leo M.;Laubach, Victor E.;Kron, Irving L.
通讯作者：
Kron, Irving L.
DOI：
10.1016/j.jtcvs.2003.08.019
发表时间：
2004-05-01
影响因子：
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作者：
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影响因子：
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影响因子：
6
作者：
Krishnadasan, B;Naidu, BV;Mulligan, MS
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DOI：
10.1152/ajprenal.00378.2004
发表时间：
2005-04-01
影响因子：
4.2
作者：
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