Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation

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Abstract

The importance of circadian factors in managing patients is poorly understood. We present two retrospective cohort studies showing that lungs reperfused between 4 and 8 AM have a higher incidence (OR 1.12; 95% CI 1.03 to 1.21; p=0.01) of primary graft dysfunction (PGD) in the first 72 hours after transplantation. Cooling of the donor lung, occurring during organ preservation, shifts the donor circadian clock causing desynchrony with the recipient. The clock protein REV-ERBα directly regulates PGD biomarkers explaining this circadian regulation while also allowing them to be manipulated with synthetic REV-ERB ligands.

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Most cited references 6

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Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation.

Jason Christie, Paul Corris, Martin Carby … (2005)

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Carbon monoxide protects the kidney through the central circadian clock and CD39.

Matheus Correa-Costa, David Gallo, Eva Csizmadia … (2018)

Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39 -/- and Per2 -/- mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.

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Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction

Ramiro Fernandez, Ankit Bharat, G R Scott Budinger … (2017)

Primary graft dysfunction is the predominant driver of mortality and graft loss after lung transplantation. Recruitment of neutrophils as a result of ischemia-reperfusion injury is thought to cause primary graft dysfunction; however, the mechanisms that regulate neutrophil influx into the injured lung are incompletely understood. We found that donor-derived intravascular nonclassical monocytes (NCMs) are retained in human and murine donor lungs used in transplantation and can be visualized at sites of endothelial injury after reperfusion. When NCMs in the donor lungs were depleted, either pharmacologically or genetically, neutrophil influx and lung graft injury were attenuated in both allogeneic and syngeneic models. Similar protection was observed when the patrolling function of donor NCMs was impaired by deletion of the fractalkine receptor CX3CR1. Unbiased transcriptomic profiling revealed up-regulation of MyD88 pathway genes and a key neutrophil chemoattractant, CXCL2, in donor-derived NCMs after reperfusion. Reconstitution of NCM-depleted donor lungs with wild-type but not MyD88-deficient NCMs rescued neutrophil migration. Donor NCMs, through MyD88 signaling, were responsible for CXCL2 production in the allograft and neutralization of CXCL2 attenuated neutrophil influx. These findings suggest that therapies to deplete or inhibit NCMs in donor lung might ameliorate primary graft dysfunction with minimal toxicity to the recipient.

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Author and article information

Journal

Journal ID (nlm-ta): Thorax

Journal ID (iso-abbrev): Thorax

Journal ID (hwp): thoraxjnl

Journal ID (publisher-id): thorax

Title: Thorax

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0040-6376

ISSN (Electronic): 1468-3296

Publication date (Print): April 2019

Publication date (Electronic): 9 October 2018

Volume: 74

Issue: 4

Pages: 413-416

Affiliations

[1 ] departmentFaculty of Biology, Medicine and Health , Manchester Academic Health Sciences Centre, The University of Manchester , Manchester, UK

[2 ] departmentDepartment of Respiratory Medicine , Manchester University NHS Foundation Trust , Manchester, UK

[3 ] departmentDepartment of Cardiothoracic Surgery , Manchester University NHS Foundation Trust , Manchester, UK

[4 ] departmentThe Toronto Lung Transplant Program , Toronto General Hospital, University Health Network, University of Toronto , Toronto, Ontario, Canada

[5 ] departmentNIHR Oxford Biomedical Research Centre , John Radcliffe Hospital , Oxford, UK

[6 ] departmentOxford Centre for Diabetes, Endocrinology and Metabolism , University of Oxford , Oxford, UK

Author notes

[Correspondence to ] Professor David W Ray and Dr John F Blaikley, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, UK; david.w.ray@ 123456manchester.ac.uk , john.blaikley@ 123456manchester.ac.uk

Author information

Hannah J Durrington http://orcid.org/0000-0002-9990-9446

Article

Publisher ID: thoraxjnl-2018-212021

DOI: 10.1136/thoraxjnl-2018-212021

PMC ID: 6484691

PubMed ID: 30301818

SO-VID: feaa4629-547a-4994-bffc-6c623a6f8c92

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This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

History

Date received : 03 May 2018

Date revision received : 06 September 2018

Date accepted : 10 September 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000341, Arthritis Research UK;

Funded by: FundRef http://dx.doi.org/10.13039/100004440, Wellcome Trust;

Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;

Funded by: FundRef http://dx.doi.org/10.13039/501100000362, Asthma UK;

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ScienceOpen disciplines: Surgery

Keywords: lung transplantation,macrophage biology

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ScienceOpen disciplines: Surgery

Keywords: lung transplantation, macrophage biology

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Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation

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Most cited references 6

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction part II: definition. A consensus statement of the International Society for Heart and Lung Transplantation.

Carbon monoxide protects the kidney through the central circadian clock and CD39.

Donor pulmonary intravascular nonclassical monocytes recruit recipient neutrophils and mediate primary lung allograft dysfunction

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