Human α1-antitrypsin improves early post-transplant lung function: Pre-clinical studies in a pig lung transplant model
Human α1-antitrypsin improves early post-transplant lung function: Pre-clinical studies in a pig lung transplant model
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DOI：
10.1016/j.healun.2016.03.006
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发表时间：
2016-07-01
影响因子：
8.9
通讯作者：
Liu, Mingyao
中科院分区：
文献类型：
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作者：
Iskender, Ilker;Sakamoto, Jin;Liu, Mingyao
背景：肺移植中新药的翻译受到小动物和人类不同生理条件的挑战。大型动物模型提供了重要的临床前证据，并为临床试验提供了最好的下一步信息。在本研究中，我们使用猪肺移植模型来确定人α(1)-抗胰蛋白酶(A1AT)是一种预防大鼠肺缺血再灌注损伤的药物，在大动物肺移植模型中是否可以减轻长期低温保存后的再灌注损伤。方法：供体肺在4℃保存24小时，然后进行肺移植。受体在再灌注前随机、盲法静脉注射A1AT(240 mg/kg；n=5)或人血清白蛋白(n=5)。在4小时再灌注期内监测同种异体移植物的气体交换功能和肺力学。结果：A1AT组再灌流4h后，肺组织气体交换明显改善。A1AT治疗改善了静态肺顺应性，显著降低了肺水肿和肺通透性。A1AT治疗抑制了循环中的炎症介质，减少了核因子-kappaB和炎症体的激活，减少了血浆凝血酶-抗凝血酶复合体的形成，减少了移植物的细胞凋亡。结论：受体再灌注前给予人A1AT可改善猪移植后即刻的肺功能。应考虑建立大动物存活模型，以支持A1AT临床试验的进一步进展，以预防肺移植中的原发移植物功能障碍。(C)2016年国际心肺移植学会。版权所有。
BACKGROUND: The translation of novel drugs in lung transplantation is challenged by different physiologic conditions between small animals and humans. Large-animal models provide important pre-clinical evidence and the next step that best informs clinical trials. In the present study, we used a pig lung transplant model to determine whether human alpha(1)-antitrypsin (A1AT), a medication shown to prevent pulmonary ischemia-reperfusion injury in rats, could attenuate reperfusion injury after prolonged hypothermic preservation in a large-animal lung transplant model.METHODS: Donor lungs were preserved for 24 hours at 4 degrees C, followed by lung transplantation. In a randomized and blinded fashion, intravenous A1AT (240 mg/kg; n = 5) or human albumin (n = 5) was administered to the recipient before reperfusion. Allograft gas exchange function and lung mechanics were monitored during a 4-hour reperfusion period. Microscopic lung injury, inflammatory response, coagulation activity, and cell death were assessed.RESULTS: Pulmonary gas exchange was significantly better during the 4-hour reperfusion period in the A1AT group. Treatment with A1AT improved static pulmonary compliance and significantly reduced pulmonary edema and lung permeability. A1AT treatment inhibited inflammatory mediators in the circulation, with reduced activation of nuclear factor-kappa B and inflammasome, reduced formation of thrombin-antithrombin complex in plasma, and reduced apoptosis in the allografts.CONCLUSIONS: Administration of human A1AT before reperfusion in recipients improved immediate post-transplant lung function in pigs. A large-animal survival model should be considered to support further advancement toward a clinical trial of A1AT to prevent primary graft dysfunction in lung transplantation. (C) 2016 International Society for Heart and Lung Transplantation. All rights reserved.