Preservation with α1-antitrypsin improves primary graft function of murine lung transplants
| Autor: | Oliver Eickelberg, Carmela Morrone, Natalia F. Smirnova, Jessica Götzfried, A. O. Yildirim, Brice Korkmaz, Dieter E. Jenne |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Male Neutrophils medicine.medical_treatment alpha-1-antitrypsin ischemia-reperfusion injury Primary Graft Dysfunction Mice Inbred Strains 030204 cardiovascular system & hematology Article Andrology 03 medical and health sciences Mice 0302 clinical medicine Proteinase 3 medicine lung transplantation Lung transplantation elastase Animals Citrates Transplantation biology medicine.diagnostic_test business.industry Pulmonary Gas Exchange Elastase Ischemia-reperfusion Injury Alpha-1-antitrypsin Animal Models Lung Transplantation Primary graft dysfunction Organ Preservation medicine.disease animal models 3. Good health proteinase 3 Disease Models Animal 030104 developmental biology Bronchoalveolar lavage Neutrophil elastase Reperfusion Injury alpha 1-Antitrypsin biology.protein Surgery Cardiology and Cardiovascular Medicine business Reperfusion injury Bronchoalveolar Lavage Fluid |
| Zdroj: | The Journal of Heart and Lung Transplantation J. Heart Lung Transpl. 37, 1021-1028 (2018) |
| ISSN: | 1557-3117 1053-2498 |
| Popis: | 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. All rights reserved. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|