Human α₁-antitrypsin improves early post-transplant lung function: Pre-clinical studies in a pig lung transplant model

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• 作者：Ilker Iskender ; MD ; MSc^a ; ^b ; Jin Sakamoto ; MD^a ; Daisuke Nakajima ; MD^a ; Huiqing Lin ; MD^a ; Manyin Chen ; MD^a ; Hyunhee Kim ; MSc ; PhD^a ; ^c ; Zehong Guan ; MSc^a ; Lorenzo Del Sorbo ; MD^a ; David Hwang ; MD ; PhD^a ; Thomas K. Waddell ; MD ; PhD^a ; ^b ; ^d ; Marcelo Cypel ; MD ; MSc^a ; ^b ; ^d ; Shaf Keshavjee ; MD ; MSc^a ; ^b ; ^d ; Mingyao Liu ; MD ; MSc^a ; ^b ; ^c ; ^d ; ^{mingyao.liu@utoronto.ca" class="auth_mail" title="E-mail the corresponding author}
• 关键词：lung transplantation ; ischemia-reperfusion injury ; preclinical trial ; α-1 antitrypsin ; primary graft dysfunction
• 刊名：Journal of Heart and Lung Transplantation
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：35
• 期：7
• 页码：913-921
• 全文大小：3106 K

文摘

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 α₁-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°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-κB 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.