The role of interleukin-1 beta as a predictive biomarker and potential therapeutic target during clinical ex vivo Lung perfusion
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).
Conclusions
Donor lungs develop a detectable and discriminatory pro-inflammatory signature in perfusate during EVLP. Blocking the IL-1β pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo.
Funding
This was a mechanistic sub-study to the multicenter trial DEVELOP-UK supported by the NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation (BTRU). The main study was funded by the NIHR Health Technology Assessment Programme and was led by Chief investigator Andrew Fisher (Newcastle) and local Principal Investigators John Dark (Newcastle), Stephen Tsui (Papworth), Nizar Yonan (Manchester), Andre Simon (Harefield), Nandor Marczin (Harefield), and Jorge Mascaro (Birmingham). This sub-study was supported by a Research Grant awarded by the United Kingdom Cystic Fibrosis Trust as a result of a donation made by the Robert Luff Foundation for research into lung transplantation. The funding organization had no role in the collection of data, its analysis or interpretation, and had no influence on the manuscript content.
History
Citation
The Journal of Heart and Lung Transplantation Volume 36, Issue 9, September 2017, Pages 985-995Version
- VoR (Version of Record)
Published in
JOURNAL OF HEART AND LUNG TRANSPLANTATIONVolume
36Issue
9Pagination
985 - 995 (11)Publisher
ELSEVIER SCIENCE INCissn
1053-2498eissn
1557-3117Available date
2017-05-12Publisher DOI
Publisher version
https://www.sciencedirect.com/science/article/pii/S105324981731793XLanguage
EnglishUsage metrics
