Dataset Information

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

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)-1? (area under the curve = 1.00, p = 0.002) and tumor necrosis factor-? (area under the curve = 0.95, p = 0.006) after 30 minutes of EVLP. IL-1? 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-1? 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-1? pathway during EVLP may reduce endothelial activation and subsequent neutrophil adhesion on reperfusion; this requires further investigation in vivo.

SUBMITTER: Andreasson ASI

PROVIDER: S-EPMC5578478 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Andreasson Anders S I ASI Borthwick Lee A LA Gillespie Colin C Jiwa Kasim K Scott Jonathan J Henderson Paul P Mayes Jonny J Romano Rosalba R Roman Marius M Ali Simi S Fildes James E JE Marczin Nandor N Dark John H JH Fisher Andrew J AJ

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20170512 9

<h4>Background</h4>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.<h4>Methods</h4>Longitudinal samples of perfusate, ...[more]

PMID: 28551353

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Project description:ImportanceThe mortality rate for individuals on the wait list for lung transplant is 15% to 25%, and still only 20% of lungs from multiorgan donors are used for lung transplant. The lung donor pool may be increased by assessing and reconditioning high-risk extended criteria donor lungs with ex vivo lung perfusion (EVLP), with similar short-term outcomes.ObjectiveTo assess the long-term outcomes of transplant recipients of donor lungs treated with EVLP.Design, setting, and participantsThis retrospective cohort single-center study was conducted from August 1, 2008, to February 28, 2017, among 706 recipients of donor lungs not undergoing EVLP and 230 recipients of donor lungs undergoing EVLP.ExposureDonor lungs undergoing EVLP.Main outcomes and measuresThe incidence of chronic lung allograft dysfunction and allograft survival during the 10-year EVLP era were the primary outcome measures. Secondary outcomes included donor characteristics, maximum predicted percentage of forced expiratory volume in 1 second, acute cellular rejection, and de novo donor-specific antibody development.ResultsThis study included 706 patients (311 women and 395 men; median age, 50 years [interquartile range, 34-61 years]) in the non-EVLP group and 230 patients (85 women and 145 men; median age, 46 years [interquartile range, 32-55 years]) in the EVLP group. The EVLP group donors had a significantly lower mean (SD) Pao2:fraction of inspired oxygen ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P < .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). More recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P < .001). There was no significant difference in time to chronic lung allograft dysfunction between the EVLP and non-EVLP group (70% vs 72% at 3 years; 56% vs 56% at 5 years; and 53% vs 36% at 9 years; log-rank P = .68) or allograft survival between the EVLP and non-EVLP groups (73% vs 72% at 3 years; 62% vs 58% at 5 years; and 50% vs 44% at 9 years; log-rank P = .97) between the 2 groups. All secondary outcomes were similar between the 2 groups.Conclusions and relevanceSince 2008, 230 of 936 lung transplants (24.6%) in the Toronto Lung Transplant Program were performed after EVLP assessment and treatment. Use of EVLP-treated lungs led to an increase in the number of patients undergoing transplantation, with comparable long-term outcomes.