Science and Research

Preservation with alpha1-antitrypsin improves primary graft function of murine lung transplants

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 alpha1-anti-trypsin (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.

  • Gotzfried, J.
  • Smirnova, N. F.
  • Morrone, C.
  • Korkmaz, B.
  • Yildirim, A. O.
  • Eickelberg, O.
  • Jenne, D. E.

Keywords

  • Primary graft dysfunction
  • alpha-1-antitrypsin
  • animal models
  • elastase
  • ischemia-reperfusion injury
  • lung transplantation
  • proteinase 3
Publication details
DOI: 10.1016/j.healun.2018.03.015
Journal: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
Pages: 1021-1028 
Number: 8
Work Type: Original
Location: CPC-M
Disease Area: ROR
Partner / Member: HMGU
Access-Number: 29776812
See publication on PubMed

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