Human Alpha-1 Antitrypsin Improves Early Posttransplant Lung Function in Pig Lung Transplant Model

Human alpha-1 antitrypsin (A1AT) has been shown to prevent pulmonary ischemia-reperfusion injury in rats. Based on this and the ability of large-animal models to provide important preclinical evidence to inform clinical trials, investigators at Toronto General Research Institute used a pig lung transplant model to determine whether human A1AT could attenuate reperfusion injury after prolonged hypothermic preservation.

Donor lungs were preserved for 24 hours at 4 degrees Celsius, 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 lung recipients before reperfusion. Allograft gas exchange function and lung mechanics were monitored during a four-hour reperfusion period. Microscopic lung injury, inflammatory response, coagulation activity and cell death were also assessed.

Pulmonary gas exchange was significantly better during the four-hour reperfusion period in the A1AT group. Treatment with A1AT improved static pulmonary compliance,significantly reduced pulmonary edema and lung permeability, inhibited inflammatory mediators in the circulation, and reduced apoptosis in the lung allografts. Based on this evidence of improved immediate posttransplant lung function in pigs, the investigators proposed consideration of a large-animal survival model to support further advancement toward a clinical trial of A1AT to prevent primary graft dysfunction in lung transplantation.