The effect of anti-inflammatory properties of mycophenolate mofetil on the development of lung reperfusion injury
The effect of anti-inflammatory properties of mycophenolate mofetil on the development of lung reperfusion injury
复制标题
DOI：
10.1016/j.healun.2005.06.005
复制
发表时间：
2005-12-01
影响因子：
8.9
通讯作者：
Mulligan, MS
中科院分区：
文献类型：
--
作者：
Farivar, AS;MacKinnon-Patterson, B;Mulligan, MS
背景资料：肺缺血再灌注损伤（LIRI）与原发性移植物衰竭和闭塞性细支气管炎的发生率增加有关。免疫抑制剂霉酚酸酯（MMF）最近已被证明可以减轻急性缺血再灌注模型中的炎症损伤，其机制目前尚不清楚。这些实验研究了在一个温暖的，在原位LIRI模型中的霉酚酸酯的影响，专注于转录调控的促炎mediators.Methods：大鼠左肺缺血90分钟，再灌注长达4小时。给药动物在缺血前2小时静脉注射10 mg/kg MMF。左肺损伤以髓过氧化物酶（MPO）含量、肺通透性指数和支气管肺泡灌洗（BAL）炎性细胞计数进行定量。用电泳迁移率变动分析法（EMSA）检测肺组织转录因子的反式激活，用酶联免疫法检测支气管肺泡灌洗液中趋化因子蛋白的含量。结果：在再灌注4 h时，霉酚酸酯能显著降低肺血管通透性指数、MPO含量和肺泡白细胞计数。激活蛋白1（AP-1）和早期生长反应1（EGR-1）反式激活显著减弱，而核因子-κ B（NF-κ B）不受影响。支气管肺泡灌洗单核细胞趋化蛋白1（MCP-1）和苦参碱诱导的中性粒细胞趋化因子（CINC）蛋白含量的减少被发现在4小时reperfusion.Conclusions：霉酚酸酯限制肺缺血-再灌注诱导的血管通透性增加和肺实质和肺泡腔中的炎性细胞隔离。这种保护作用是在转录水平上通过减弱早期EGR-1和AP-1的反式激活来介导的，这被发现与晚期MCP-1和CINC蛋白分泌减少有关。与影响NF-κ B活化的药物联合使用MMF可进一步保护肺免受再灌注损伤，因为多种炎症途径受到抑制。
Background: Lung ischemia-reperfusion injury (LIRI) is associated with an increased incidence of both primary graft failure and obliterative bronchiolitis. The immunosuppressant mycophenolate mofetil (MMF) has recently been shown to attenuate inflammatory injury in acute ischemia-reperfusion models via a mechanism that is presently unclear. These experiments studied the effects of MMF in a warm, in situ LIRI model, focusing on transcriptional regulation of pro-inflammatory mediators.Methods: Left lungs of rats were rendered ischemic for 90 minutes and reperfused for up to 4 hours. Treated animals received 10 mg/kg of intravenous MMF at 2 hours before ischemia. Left lung injury was quantitated by myeloperoxidase (MPO) content, permeability indices and bronchoalveolar lavage (BAL) inflammatory cell counts. Lungs were analyzed by electrophoretic mobility shift assay (EMSA) for transcription factor transactivation and by enzyme-linked immunoassay for BAL chemokine protein content.Results: MMF significantly reduced lung vascular permeability indices, MPO content and alveolar leukocyte counts at 4 hours of reperfusion. There was significant attenuation of activator protein 1 (AP-1) and early growth response 1 (EGR-1) transactivation, whereas nuclear factor-kappa B (NF-kappa B) was unaffected. Reductions in bronchoalveolar lavage monocyte chemoattractant protein 1 (MCP-1) and cytokine-induced neutrophil chemoattractant (CINC) protein content were found at 4 hours of reperfusion.Conclusions: MMF limits lung ischemia-reperfusion-induced increases in vascular permeability and inflammatory cell sequestration in lung parenchyma and alveolar spaces. The protection is mediated at the transcriptional level via an attenuation of early EGR-1 and AP-1 transactivation, which was found to be associated with reduced late MCP-1 and CINC protein secretion. The use of MMF in concert with an agent that affects NF-kappa B activation may provide even further protection against lung reperfusion injury as multiple inflammatory pathways are inhibited.