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.
N1 - Publisher Copyright:
© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2019/5
Y1 - 2019/5
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
U2 - 10.1111/ajt.15232
DO - 10.1111/ajt.15232
M3 - Article
C2 - 30582269
AN - SCOPUS:85060657116
SN - 1600-6135
VL - 19
SP - 1464
EP - 1477
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 5
ER -