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

6 Citations (Scopus)

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
Pages (from-to)1464-1477
Number of pages14
JournalAmerican Journal of Transplantation
Volume19
Issue number5
DOIs
Publication statusPublished - May 2019
Externally publishedYes

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)

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  • Cite this

    Scozzi, D., Ibrahim, M., Liao, F., Lin, X., Hsiao, H. M., Hachem, R., Tague, L. K., Ricci, A., Kulkarni, H. S., Huang, H. J., Sugimoto, S., Krupnick, A. S., Kreisel, D., & Gelman, A. E. (2019). Mitochondrial damage–associated molecular patterns released by lung transplants are associated with primary graft dysfunction. American Journal of Transplantation, 19(5), 1464-1477. https://doi.org/10.1111/ajt.15232