Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction

Davide Scozzi, Mohsen Ibrahim, Fuyi Liao, Xue Lin, Hsi Min Hsiao, Ramsey Hachem, Laneshia K. Tague, Alberto Ricci, Hrishikesh S. Kulkarni, Howard J. Huang, Seiichiro Sugimoto, Alexander S. Krupnick, Daniel Kreisel, Andrew E. Gelman

Research output: Contribution to journalArticle

Abstract

Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage–associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)–induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.

Original languageEnglish
JournalAmerican Journal of Transplantation
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Primary Graft Dysfunction
Mitochondria
Peptide Receptors
Transplants
Neutrophils
Lung
Mitochondrial DNA
Transendothelial and Transepithelial Migration
N-Formylmethionine Leucyl-Phenylalanine
Lung Transplantation
Wounds and Injuries
Pulmonary Edema
Chemotaxis
Intensive Care Units
Reactive Oxygen Species
Tissue Donors

Keywords

  • animal models
  • basic (laboratory) research/science
  • cellular biology
  • clinical research/practice
  • immunobiology
  • innate immunity
  • ischemia-reperfusion injury (IRI)
  • lung (allograft) function/dysfunction
  • lung transplantation/pulmonology
  • mouse

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

Cite this

Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction. / Scozzi, Davide; Ibrahim, Mohsen; Liao, Fuyi; Lin, Xue; Hsiao, Hsi Min; Hachem, Ramsey; Tague, Laneshia K.; Ricci, Alberto; Kulkarni, Hrishikesh S.; Huang, Howard J.; Sugimoto, Seiichiro; Krupnick, Alexander S.; Kreisel, Daniel; Gelman, Andrew E.

In: American Journal of Transplantation, 01.01.2018.

Research output: Contribution to journalArticle

Scozzi, D, Ibrahim, M, Liao, F, Lin, X, Hsiao, HM, Hachem, R, Tague, LK, Ricci, A, Kulkarni, HS, Huang, HJ, Sugimoto, S, Krupnick, AS, Kreisel, D & Gelman, AE 2018, 'Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction', American Journal of Transplantation. https://doi.org/10.1111/ajt.15232
Scozzi, Davide ; Ibrahim, Mohsen ; Liao, Fuyi ; Lin, Xue ; Hsiao, Hsi Min ; Hachem, Ramsey ; Tague, Laneshia K. ; Ricci, Alberto ; Kulkarni, Hrishikesh S. ; Huang, Howard J. ; Sugimoto, Seiichiro ; Krupnick, Alexander S. ; Kreisel, Daniel ; Gelman, Andrew E. / Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction. In: American Journal of Transplantation. 2018.
@article{9fe8ba479da943edb98ca810c3b61e0a,
title = "Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction",
abstract = "Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage–associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)–induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.",
keywords = "animal models, basic (laboratory) research/science, cellular biology, clinical research/practice, immunobiology, innate immunity, ischemia-reperfusion injury (IRI), lung (allograft) function/dysfunction, lung transplantation/pulmonology, mouse",
author = "Davide Scozzi and Mohsen Ibrahim and Fuyi Liao and Xue Lin and Hsiao, {Hsi Min} and Ramsey Hachem and Tague, {Laneshia K.} and Alberto Ricci and Kulkarni, {Hrishikesh S.} and Huang, {Howard J.} and Seiichiro Sugimoto and Krupnick, {Alexander S.} and Daniel Kreisel and Gelman, {Andrew E.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1111/ajt.15232",
language = "English",
journal = "American Journal of Transplantation",
issn = "1600-6135",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction

AU - Scozzi, Davide

AU - Ibrahim, Mohsen

AU - Liao, Fuyi

AU - Lin, Xue

AU - Hsiao, Hsi Min

AU - Hachem, Ramsey

AU - Tague, Laneshia K.

AU - Ricci, Alberto

AU - Kulkarni, Hrishikesh S.

AU - Huang, Howard J.

AU - Sugimoto, Seiichiro

AU - Krupnick, Alexander S.

AU - Kreisel, Daniel

AU - Gelman, Andrew E.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage–associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)–induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.

AB - Primary graft dysfunction (PGD) is a major limitation in short- and long-term lung transplant survival. Recent work has shown that mitochondrial damage–associated molecular patterns (mtDAMPs) can promote solid organ injury, but whether they contribute to PGD severity remains unclear. We quantitated circulating plasma mitochondrial DNA (mtDNA) in 62 patients, before lung transplantation and shortly after arrival to the intensive care unit. Although all recipients released mtDNA, high levels were associated with severe PGD development. In a mouse orthotopic lung transplant model of PGD, we detected airway cell-free damaged mitochondria and mtDNA in the peripheral circulation. Pharmacologic inhibition or genetic deletion of formylated peptide receptor 1 (FPR1), a chemotaxis sensor for N-formylated peptides released by damaged mitochondria, inhibited graft injury. An analysis of intragraft neutrophil-trafficking patterns reveals that FPR1 enhances neutrophil transepithelial migration and retention within airways but does not control extravasation. Using donor lungs that express a mitochondria-targeted reporter protein, we also show that FPR1-mediated neutrophil trafficking is coupled with the engulfment of damaged mitochondria, which in turn triggers reactive oxygen species (ROS)–induced pulmonary edema. Therefore, our data demonstrate an association between mtDAMP release and PGD development and suggest that neutrophil trafficking and effector responses to damaged mitochondria are drivers of graft damage.

KW - animal models

KW - basic (laboratory) research/science

KW - cellular biology

KW - clinical research/practice

KW - immunobiology

KW - innate immunity

KW - ischemia-reperfusion injury (IRI)

KW - lung (allograft) function/dysfunction

KW - lung transplantation/pulmonology

KW - mouse

UR - http://www.scopus.com/inward/record.url?scp=85060657116&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060657116&partnerID=8YFLogxK

U2 - 10.1111/ajt.15232

DO - 10.1111/ajt.15232

M3 - Article

C2 - 30582269

AN - SCOPUS:85060657116

JO - American Journal of Transplantation

JF - American Journal of Transplantation

SN - 1600-6135

ER -