Abstract | BACKGROUND: 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.
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Authors | Matthew 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 |
Journal | Transplantation
(Transplantation)
Vol. 99
Issue 12
Pg. 2494-503
(Dec 2015)
ISSN: 1534-6080 [Electronic] United States |
PMID | 26262504
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Adenosine A2 Receptor Agonists
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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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