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

J Heart Lung Transplant. 2017 Sep;36(9):985-995. doi: 10.1016/j.healun.2017.05.012. Epub 2017 May 12.

Andreasson ASI¹, Borthwick LA², Gillespie C³, Jiwa K⁴, Scott J², Henderson P⁴, Mayes J², Romano R⁵, Roman M⁶, Ali S², Fildes JE⁷, Marczin N⁶, Dark JH¹, Fisher AJ⁸; DEVELOP-UK Investigators.

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.

Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved. KEYWORDS: biomarker; ex vivo lung perfusion; interleukin-1β; lung injury; lung transplantation.  PMID: 28551353 PMCID: PMC5578478 DOI: 10.1016/j.healun.2017.05.012  Free PMC Article