L-Alanyl-L-Glutamine Alleviated Ischemia-Reperfusion Injury and Primary Graft Dysfunction in Rat Lung Transplants

Abstract

Background. Concern of ischemia-reperfusion injury reduces utilization of donor lungs. We hypothesized adding L-alanyl-L-glutamine (L-AG) to preservation solution may protect donor lungs from ischemia-reperfusion injury through its multiple cytoprotective effects. Methods. A lung transplantation cell culture model was used on human lung epithelial cells and pulmonary microvascular endothelial cells, and the effects of adding different concentrations of L-AG on basic cellular function were tested. Rat donor lungs were preserved at 4 °C with 8 mmol/L L-AG for 12 h followed by 4 h reperfusion or monitored for 3 d. Lung function, lung histology, inflammation, and cell death biomarker were tested. Computerized tomography scan was used and metabolomic analysis was performed on lung tissues. Results. Cold preservation with L-AG improved cell viability and inhibited apoptosis in cell culture. Rat donor lungs treated with L-AG during cold storage showed decreased peak airway pressure, higher dynamic compliance and oxygenation ability, reduced lung injury, apoptosis, and oxidative stress during reperfusion. L-AG treatment significantly changed 130 metabolites during reperfusion, with enhanced amino acid biosynthesis and tricarboxylic acid cycle. Furthermore, cold storage with L-AG decreased primary graft dysfunction grade, improved oxygenation, reduced pulmonary atelectasis, sign of infection, and pneumothorax in a rat left lung transplant 3-d survival model. Conclusions. Adding L-AG to cold preservation solution reduced lung injury and alleviated primary graft dysfunction by inhibiting inflammation, oxidative stress, and cell death with modified metabolic activities.