Targeting Circulating Leukocytes and Pyroptosis during Ex Vivo Lung Perfusion Improves Lung Preservation.

Transplantation. 2017 Apr 27. doi: 10.1097/TP.0000000000001798. [Epub ahead of print] Targeting Circulating Leukocytes and Pyroptosis during Ex Vivo Lung Perfusion Improves Lung Preservation.

Noda K¹, Tane S, Haam SJ, D’Cunha J, Hayanga AJ, Luketich JD, Shigemura N. (Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

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). Following EVLP, lung grafts were transplanted, and post-transplant 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 following lung transplantation.

PMID: 28452921 DOI: 10.1097/TP.0000000000001798