The role of interleukin-1β as a predictive biomarker and potential therapeutic target during clinical ex vivo lung perfusion
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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 (R(2) = 0.68, p < 0.001) and to a lesser degree upregulation of intracellular adhesion molecule-1 (R(2) = 0.30, p = 0.001) and E-selectin (R(2) = 0.29, p = 0.001) in conditioned HPMECs and neutrophil adhesion to conditioned HPMECs (R(2) = 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.
Date Issued
2017-05-12
Date Acceptance
2017-05-09
Citation
Journal of Heart and Lung Transplantation, 2017, 36 (9), pp.985-995
ISSN
1053-2498
Publisher
Elsevier
Start Page
985
End Page
995
Journal / Book Title
Journal of Heart and Lung Transplantation
Volume
36
Issue
9
Copyright Statement
© 2017 The Authors. Published by Elsevier Inc. on behalf of International Society for Heart and Lung Transplantation. All
rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor
Royal Brompton & Harefield NHS Foundation Trust
Cystic Fibrosis Trust
National Institute for Health Research
Royal Brompton & Harefield NHS Foundation Trust
Identifier
PII: S1053-2498(17)31793-X
Grant Number
WSSA_P41866
WSSA_P40127
N/A
WSSA_P44244
Subjects
biomarker
ex vivo lung perfusion
interleukin-1β
lung injury
lung transplantation
Publication Status
Published