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Preservation with alpha(1)-antitrypsin improves primary graft function of murine lung transplants.

J. Heart Lung Transpl. 37, 1021-1028 (2018)
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BACKGROUND: Vascular damage and primary graft dysfunction increase with prolonged preservation times of transplanted donor lungs. Hence, storage and conservation of donated lungs in protein-free, dextran-containing electrolyte solutions, like Perfadex, is limited to about 6 hours. We hypothesized that transplanted lungs are protected against neutrophil-mediated proteolytic damage by adding alpha(1)-antitrypsin (AAT), a highly abundant human plasma proteinase inhibitor, to Perfadex.METHODS: A realistic clinically oriented murine model of lung transplantation was used to simulate the ischemia-reperfusion process. Lung grafts were stored at 4 degrees C in Perfadex solution supplemented with AAT or an AAT mutant devoid of elastase-inhibiting activity for 18 hours. We examined wild-type and proteinase 3/neutrophil elastase (PR3/NE) double-deficient mice as graft recipients. Gas exchange function and infiltrating neutrophils of the transplanted lung, as well as protein content and neutrophil numbers in the bronchoalveolar lavage fluid, were determined.RESULTS: AAT as a supplement to Perfadex reduced the extent of primary graft dysfunction and early neutrophil responses after extended storage for 18 hours at 4 degrees C and 4-hour reperfusion in the recipients. Double-knockout recipients that lack elastase-like activities in neutrophils were also protected from early reperfusion injury, but not lung grafts that were perfused with a reactive center mutant of AAT devoid of elastase-inhibiting activity.CONCLUSIONS: PR3 and NE, the principal targets of AAT, are major triggers of post-ischemic reperfusion damage. Their effective inhibition in the graft and recipient is a promising strategy for organ usage after storage for >6 hours. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Primary Graft Dysfunction ; Ischemia-reperfusion Injury ; Alpha-1-antitrypsin ; Elastase ; Proteinase 3 ; Animal Models ; Lung Transplantation; Ischemia-reperfusion Injury; Neutrophil Serine Proteases; Inflammatory Response; Cell Apoptosis; Alpha-1-antitrypsin; Aprotinin; Elastase; Proteinase-3; Dysfunction; Inhibition
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