Sharma Ashish K, Linden Joel, Kron Irving L, Laubach Victor E
Department of Surgery, University of Virginia Health System, Charlottesville, Virginia, USA.
Respir Res. 2009 Jun 26;10(1):58. doi: 10.1186/1465-9921-10-58.
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-alpha, 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.
肺缺血再灌注（IR）损伤会导致严重的发病率和死亡率，这仍然是肺移植后的一个主要障碍。然而，肺细胞群体的各个亚群在肺IR损伤发病机制中的作用以及细胞保护机制仍有待阐明。在本研究中，我们使用分离的、缓冲液灌注的小鼠肺模型，研究了腺苷A2A受体（A2AAR）激活对IR损伤后肺驻留细胞的影响。
为评估A2AAR激活的保护作用，研究了三组C57BL/6J小鼠：假手术组（灌注2小时，无缺血）、IR组（1小时缺血+1小时再灌注）和IR+ATL313组，其中在缺血后的再灌注缓冲液中加入了特异性A2AAR激动剂ATL313。在有或没有ATL313预处理的A2AAR基因敲除小鼠IR损伤后，也进行了肺损伤参数和肺功能研究。使用缓冲液灌注的离体肺系统评估肺功能。通过评估支气管肺泡灌洗液中的肺水肿、血管通透性、细胞因子/趋化因子激活和髓过氧化物酶水平来测量肺损伤。
IR后，C57BL/6J野生型小鼠的肺表现出明显的功能障碍（气道阻力增加、肺动脉压升高和肺顺应性降低）和明显的损伤（血管通透性和水肿增加）。ATL313治疗显著减轻了IR后的肺损伤和功能障碍。IR后TNF-α、KC（CXCL1）、MIP-2（CXCL2）和RANTES（CCL5）显著诱导，ATL313治疗也使其减轻。A2AAR基因敲除小鼠的肺在IR后也表现出明显的功能障碍、损伤和细胞因子/趋化因子产生，但ATL313对这些小鼠没有影响。
A2AAR的特异性激活通过减轻炎症为肺IR损伤提供了强大的保护作用。这种保护作用在没有循环血液的情况下发生，从而表明A2AAR激活对肺泡巨噬细胞等肺驻留细胞具有保护作用。特异性A2AAR激活可能是预防或治疗移植患者肺移植功能障碍的一个有前景的治疗靶点。
