The molecular features of chronic lung allograft dysfunction in lung transplant airway mucosa

Kieran Halloran, Martina Mackova, Michael D. Parkes, Alim Hirji, Justin Weinkauf, Irina L. Timofte, Greg I. Snell, Glen P. Westall, Robert Lischke, Andrea Zajacova, Jan Havlin, 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

Abstract

Background: Many lung transplants fail due to chronic lung allograft dysfunction (CLAD). We recently showed that transbronchial biopsies (TBBs) from CLAD patients manifest severe parenchymal injury and dedifferentiation, distinct from time-dependent changes. The present study explored time-selective and CLAD-selective transcripts in mucosal biopsies from the third bronchial bifurcation (3BMBs), compared to those in TBBs. Methods: We used genome-wide microarray measurements in 324 3BMBs to identify CLAD-selective changes as well as time-dependent changes and develop a CLAD classifier. CLAD-selective transcripts were identified with linear models for microarray data (limma) and were used to build an ensemble of 12 classifiers to predict CLAD. Hazard models and random forests were then used to predict the risk of graft loss using the CLAD classifier, transcript sets associated with rejection, injury, and time. Results: T cell-mediated rejection and donor-specific antibody were increased in CLAD 3BMBs but most had no rejection. Like TBBs, 3BMBs showed a time-dependent increase in transcripts expressed in inflammatory cells that was not associated with CLAD or survival. Also like TBBs, the CLAD-selective transcripts in 3BMBs reflected severe parenchymal injury and dedifferentiation, not inflammation or rejection. While 3BMBs and TBBs did not overlap in their top 20 CLAD-selective transcripts, many CLAD-selective transcripts were significantly increased in both for example LOXL1, an enzyme controlling matrix remodeling. In Cox models for one-year survival, the 3BMB CLAD-selective transcripts and CLAD classifier predicted graft loss and correlated with CLAD stage. Many 3BMB CLAD-selective transcripts were also increased by injury in kidney transplants and correlated with decreased kidney survival, including LOXL1. Conclusions: Mucosal and transbronchial biopsies from CLAD patients reveal a diffuse molecular injury and dedifferentiation state that impacts prognosis and correlates with the physiologic disturbances. CLAD state in lung transplants shares features with failing kidney transplants, indicating elements shared by the injury responses of distressed organs.

Original languageEnglish (US)
JournalJournal of Heart and Lung Transplantation
DOIs
StateAccepted/In press - 2022

Keywords

  • airway
  • chronic lung allograft dysfunction
  • gene expression
  • injury

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Fingerprint

Dive into the research topics of 'The molecular features of chronic lung allograft dysfunction in lung transplant airway mucosa'. Together they form a unique fingerprint.

Cite this