Monday, 11 September 2017 11:39

The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex vivo lung perfusion



Anders S.I. Andreasson,a,b Lee A. Borthwick,b Colin Gillespie,c Kasim Jiwa,a Jonathan Scott,c,b Paul Henderson,a Jonny Mayes,b Rosalba Romano,d Marius Roman,e Simi Ali,b James E. Fildes,f,g Nandor Marczin,d John H. Dark,a,b Andrew J. Fishera,b

aInstitute of Transplantation, Freeman Hospital, Newcastle upon Tyne, UK

bInstitute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

cSchool of Mathematics & Statistics, Newcastle University, Newcastle upon Tyne, UK

dImperial College London, London, UK

ePapworth Hospital, Cambridge, UK

fUniversity Hospital of South Manchester, Manchester, UK

gManchester Collaborative Centre for Inflammation Research, University of Manchester, Manchester, UK



Background: Extended criteria donor lungs deemed unsuitable for immediate transplantation can be reconditioned using ex vivo lung perfusion (EVLP). Objective identification of which donor lungs can be successfully reconditioned and will function well post-operatively has not been established. This study assessed the predictive value of markers of inflammation and tissue injury in donor lungs undergoing EVLP as part of the DEVELOP-UK study.

Methods: Longitudinal samples of perfusate, bronchoalveolar lavage, and tissue from 42 human donor lungs undergoing clinical EVLP assessments were analyzed for markers of inflammation and tissue injury. Levels were compared according to EVLP success and post-transplant outcomes. Neutrophil adhesion to human pulmonary microvascular endothelial cells (HPMECs) conditioned with perfusates from EVLP assessments was investigated on a microfluidic platform.

Results: The most effective markers to differentiate between in-hospital survival and non-survival post-transplant were perfusate interleukin (IL)-1β (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-α (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1β levels in perfusate correlated with upregulation of intracellular adhesion molecule-1 in donor lung vasculature (R2 = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R2 = 0.30, p = 0.001) and E-selectin (R2 = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R2 = 0.33, p < 0.001). Neutralization of IL-1β in perfusate effectively inhibited neutrophil adhesion to conditioned HPMECs (91% reduction, p = 0.002).