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Ex Vivo Perfusion With Adenosine A2A Receptor Agonist Enhances Rehabilitation of Murine Donor Lungs After Circulatory Death.

AbstractBACKGROUND:
Ex vivo lung perfusion (EVLP) enables assessment and rehabilitation of marginal donor lungs before transplantation. We previously demonstrated that adenosine A2A receptor (A2AR) agonism attenuates lung ischemia-reperfusion injury. The current study utilizes a novel murine EVLP model to test the hypothesis that A2AR agonist enhances EVLP-mediated rehabilitation of donation after circulatory death (DCD) lungs.
METHODS:
Mice underwent euthanasia and 60 minutes warm ischemia, and lungs were flushed with Perfadex and underwent cold static preservation (CSP, 60 minutes). Three groups were studied: no EVLP (CSP), EVLP with Steen solution for 60 minutes (EVLP), and EVLP with Steen solution supplemented with ATL1223, a selective A2AR agonist (EVLP + ATL1223). Lung function, wet/dry weight, cytokines and neutrophil numbers were measured. Microarrays were performed using the Affymetrix GeneChip Mouse Genome 430A 2.0 Array.
RESULTS:
Ex vivo lung perfusion significantly improved lung function versus CSP, which was further, significantly improved by EVLP + ATL1223. Lung edema, cytokines, and neutrophil counts were reduced after EVLP and further, significantly reduced after EVLP + ATL1223. Gene array analysis revealed differential expression of 1594 genes after EVLP, which comprise canonical pathways involved in inflammation and innate immunity including IL-1, IL-8, IL-6, and IL-17 signaling. Several pathways were uniquely regulated by EVLP + ATL1223 including the downregulation of genes involved in IL-1 signaling, such as ADCY9, ECSIT, IRAK1, MAPK12, and TOLLIP.
CONCLUSIONS:
Ex vivo lung perfusion modulates proinflammatory genes and reduces pulmonary dysfunction, edema, and inflammation in DCD lungs, which are further reduced by A2AR agonism. This murine EVLP model provides a novel platform to study rehabilitative mechanisms of DCD lungs.
AuthorsMatthew L Stone, Ashish K Sharma, Valeria R Mas, Ricardo C Gehrau, Daniel P Mulloy, Yunge Zhao, Christine L Lau, Irving L Kron, Mary E Huerter, Victor E Laubach
JournalTransplantation (Transplantation) Vol. 99 Issue 12 Pg. 2494-503 (Dec 2015) ISSN: 1534-6080 [Electronic] United States
PMID26262504 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Adenosine A2 Receptor Agonists
Topics
  • Adenosine A2 Receptor Agonists (pharmacology)
  • Animals
  • Disease Models, Animal
  • Extracorporeal Circulation
  • Lung (blood supply)
  • Lung Transplantation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Perfusion (methods)
  • Reperfusion Injury (rehabilitation)

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