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Targeting Circulating Leukocytes and Pyroptosis During Ex Vivo Lung Perfusion Improves Lung Preservation

Authors
Noda, K; Tane, S; Haam, SJ; D'Cunha, J; Hayanga, AJ; Luketich, JD; Shigemura, N
Citation
Transplantation, 101(12):2841-2849, 2017
Journal Title
Transplantation
ISSN
0041-13371534-6080
Abstract
BACKGROUND: The role of the circulating leukocytes in lungs and their relationship with circulating proinflammatory cytokines during ischemia-reperfusion injury is not well understood. Using ex vivo lung perfusion (EVLP) to investigate the pathophysiology of isolated lungs, we aimed to identify a therapeutic target to optimize lung preservation leading to successful lung transplantation.
METHODS: Rat heart-lung blocks were placed on EVLP for 4 hours with or without a leukocyte-depleting filter (LF). After EVLP, lung grafts were transplanted, and posttransplant outcomes were compared.
RESULTS: Lung function was significantly better in lung grafts on EVLP with a LF than in lungs on EVLP without a LF. The interleukin (IL)-6 levels in the lung grafts and EVLP perfusate were also significantly lower after EVLP with a LF. Interestingly, IL-6 levels in the perfusate did not increase after the lungs were removed from the EVLP circuit, indicating that the cells trapped by the LF were not secreting IL-6. The trapped cells were analyzed with flow cytometry to detect apoptosis and pyroptosis: 26% were pyroptotic (Caspase-1-positive). After transplantation, there was better graft function and less inflammatory response if a LF was used or a caspase-1 inhibitor was administered during EVLP.
CONCLUSIONS: Our data demonstrated that circulating leukocytes derived from donor lungs, and not circulating proinflammatory cytokines substantially impaired the quality of lung grafts through caspase-1-induced pyroptotic cell death during EVLP. Removing these cells with a LF and/or inhibiting pyroptosis of the cells can be a new therapeutic approach leading to long-term success after lung transplantation.
MeSH terms
AnimalsCardiopulmonary BypassCaspase 1/metabolismCytokines/metabolismHumansInflammationInterleukin-6/metabolismLeukocytes/cytology*Leukocytes/metabolismLung/pathology*Lung/physiology*Lung Transplantation/methods*MaleMicrocirculationOrgan Preservation/methods*PerfusionPyroptosis*RatsRats, Inbred LewRespiratory Function TestsTreatment Outcome
DOI
10.1097/TP.0000000000001798
PMID
28452921
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Thoracic & Cardiovascular Surgery
AJOU Authors
함, 석진
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