Transcripts associated with chronic lung allograft dysfunction in transbronchial biopsies of lung transplants

Michael D. Parkes, Kieran Halloran, Alim Hirji, Shane Pon, Justin Weinkauf, Irina L. Timofte, Greg I. Snell, Glen P. Westall, Jan Havlin, Robert Lischke, Andrea Zajacová, Ramsey Hachem, Daniel Kreisel, Deborah Levine, Bartosz Kubisa, Maria Piotrowska, Stephen Juvet, Shaf Keshavjee, Peter Jaksch, Walter KlepetkoPhilip F. Halloran

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Transplanted lungs suffer worse outcomes than other organ transplants with many developing chronic lung allograft dysfunction (CLAD), diagnosed by physiologic changes. Histology of transbronchial biopsies (TBB) yields little insight, and the molecular basis of CLAD is not defined. We hypothesized that gene expression in TBBs would reveal the nature of CLAD and distinguish CLAD from changes due simply to time posttransplant. Whole-genome mRNA profiling was performed with microarrays in 498 prospectively collected TBBs from the INTERLUNG study, 90 diagnosed as CLAD. Time was associated with increased expression of inflammation genes, for example, CD1E and immunoglobulins. After correcting for time, CLAD manifested not as inflammation but as parenchymal response-to-wounding, with increased expression of genes such as HIF1A, SERPINE2, and IGF1 that are increased in many injury and disease states and cancers, associated with development, angiogenesis, and epithelial response-to-wounding in pathway analysis. Fibrillar collagen genes were increased in CLAD, indicating matrix changes, and normal transcripts were decreased—dedifferentiation. Gene-based classifiers predicted CLAD with AUC 0.70 (no time-correction) and 0.87 (time-corrected). CLAD related gene sets and classifiers were strongly prognostic for graft failure and correlated with CLAD stage. Thus, in TBBs, molecular changes indicate that CLAD primarily reflects severe parenchymal injury-induced changes and dedifferentiation.

Original languageEnglish (US)
JournalAmerican Journal of Transplantation
DOIs
StateAccepted/In press - 2021
Externally publishedYes

Keywords

  • basic (laboratory) research / science
  • biopsy
  • lung (allograft) function / dysfunction
  • lung failure / injury
  • lung transplantation / pulmonology
  • rejection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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