Department of Surgery, University of Virginia Health System, Charlottesville, VA 22908, USA.
J Thorac Cardiovasc Surg. 2010 Oct;140(4):871-7. doi: 10.1016/j.jtcvs.2010.06.051. Epub 2010 Jul 24.
Ischemia-reperfusion injury after lung transplantation remains a major source of morbidity and mortality. Adenosine receptors have been implicated in both pro- and anti-inflammatory roles in ischemia-reperfusion injury. This study tests the hypothesis that the adenosine A(2B) receptor exacerbates the proinflammatory response to lung ischemia-reperfusion injury.
An in vivo left lung hilar clamp model of ischemia-reperfusion was used in wild-type C57BL6 and adenosine A(2B) receptor knockout mice, and in chimeras created by bone marrow transplantation between wild-type and adenosine A(2B) receptor knockout mice. Mice underwent sham surgery or lung ischemia-reperfusion (1 hour ischemia and 2 hours reperfusion). At the end of reperfusion, lung function was assessed using an isolated buffer-perfused lung system. Lung inflammation was assessed by measuring proinflammatory cytokine levels in bronchoalveolar lavage fluid, and neutrophil infiltration was assessed via myeloperoxidase levels in lung tissue.
Compared with wild-type mice, lungs of adenosine A(2B) receptor knockout mice were significantly protected after ischemia-reperfusion, as evidenced by significantly reduced pulmonary artery pressure, increased lung compliance, decreased myeloperoxidase, and reduced proinflammatory cytokine levels (tumor necrosis factor-α; interleukin-6; keratinocyte chemoattractant; regulated on activation, normal T-cell expressed and secreted; and monocyte chemotactic protein-1). Adenosine A(2B) receptor knockout → adenosine A(2B) receptor knockout (donor → recipient) and wild-type → adenosine A(2B) receptor knockout, but not adenosine A(2B) receptor knockout → wild-type, chimeras showed significantly improved lung function after ischemia-reperfusion.
These results suggest that the adenosine A(2B) receptor plays an important role in mediating lung inflammation after ischemia-reperfusion by stimulating cytokine production and neutrophil chemotaxis. The proinflammatory effects of adenosine A(2B) receptor seem to be derived by adenosine A(2B) receptor activation primarily on resident pulmonary cells and not bone marrow-derived cells. Adenosine A(2B) receptor may provide a therapeutic target for prevention of ischemia-reperfusion-related graft dysfunction in lung transplant recipients.
肺移植后缺血再灌注损伤仍然是发病率和死亡率的主要来源。腺苷受体在缺血再灌注损伤的促炎和抗炎作用中都有涉及。本研究检验了这样一个假设，即腺苷 A（2B）受体加剧了肺缺血再灌注损伤的促炎反应。
在野生型 C57BL6 和腺苷 A（2B）受体敲除小鼠的活体左肺门夹钳模型中，以及在野生型和腺苷 A（2B）受体敲除小鼠之间的骨髓移植嵌合体中，使用了体内左肺门夹钳模型的缺血再灌注。小鼠接受假手术或肺缺血再灌注（1 小时缺血和 2 小时再灌注）。在再灌注结束时，使用分离的缓冲液灌注肺系统评估肺功能。通过测量支气管肺泡灌洗液中的促炎细胞因子水平来评估肺炎症，通过肺组织中的髓过氧化物酶水平来评估中性粒细胞浸润。
与野生型小鼠相比，腺苷 A（2B）受体敲除小鼠的肺在缺血再灌注后受到明显保护，表现为肺动脉压显著降低、肺顺应性增加、髓过氧化物酶减少和促炎细胞因子水平降低（肿瘤坏死因子-α；白细胞介素-6；角质形成细胞化学引诱物；调节激活正常 T 细胞表达和分泌；单核细胞趋化蛋白-1）。腺苷 A（2B）受体敲除→腺苷 A（2B）受体敲除（供体→受体）和野生型→腺苷 A（2B）受体敲除，但不是腺苷 A（2B）受体敲除→野生型嵌合体，在缺血再灌注后显示出明显改善的肺功能。
这些结果表明，腺苷 A（2B）受体通过刺激细胞因子产生和中性粒细胞趋化作用，在介导缺血再灌注后的肺炎症中发挥重要作用。腺苷 A（2B）受体的促炎作用似乎主要来源于驻留肺细胞而非骨髓来源细胞的腺苷 A（2B）受体激活。腺苷 A（2B）受体可能为预防肺移植受者缺血再灌注相关移植物功能障碍提供治疗靶点。
