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



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.



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.



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.
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Institute of Medical Science.
Ilker
I
Iskender
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network.
Jin
J
Sakamoto
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network.
Daisuke
D
Nakajima
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network.
Huiqing
H
Lin
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network.
Manyin
M
Chen
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Physiology.
Hyunhee
H
Kim
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network.
Zehong
Z
Guan
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network.
Lorenzo
L
Del Sorbo
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network.
David
D
Hwang
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Institute of Medical Science; Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Thomas K
TK
Waddell
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Institute of Medical Science; Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Marcelo
M
Cypel
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Institute of Medical Science; Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Shaf
S
Keshavjee
Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network; Institute of Medical Science; Physiology; Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: mingyao.liu@utoronto.ca.
Mingyao
M
Liu
D000818:Animals; D000990:Antithrombin III; D006801:Humans; D008168:Lung; D016040:Lung Transplantation; D010447:Peptide Hydrolases; D051381:Rats; D015427:Reperfusion Injury; D013552:Swine
C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases
ischemia-reperfusion injury; lung transplantation; preclinical trial; primary graft dysfunction; α-1 antitrypsin