Abstract
BACKGROUND: Chronic lung allograft dysfunction (CLAD) is a major contributor to poor long-term survival after lung transplantation (LTx). There is a paucity of validated tissue biomarkers which limits the early detection of CLAD. The aim of this study was to discover novel tissue proteins in CLAD. METHODS: A longitudinal cohort study analyzed 15 tissue specimens from 2 groups of bilateral LTx recipients; those with CLAD (n = 3) and those without CLAD (n = 3). In both groups, transbronchial biopsies (TBBx) were retrieved from 2 timepoints; stable surveillance at 90 d after transplant, and during episodes of acute lung allograft dysfunction. In the CLAD cohort, additional tissue from explant CLAD lungs collected at retransplantation was analyzed. Proteomics analysis and immunohistochemistry were used to identify and validate differentially expressed proteins. RESULTS: Tissue upregulation of a number of proteins including SerpinB1, SerpinH1, Cofilin 1, MUC1, COL15A1, COL4A4, and Coronin1B was found in recipients with CLAD. This finding was present when comparing CLAD onset and explant pathology to stable surveillance among recipients with CLAD and evident when compared with recipients without CLAD. Most of the upregulated tissue proteins in patients with CLAD had collectively critical roles in leukocytes migration and activation, inflammation, free radicals production and oxidative stress, epithelial-mesenchymal transition, myofibroblasts activation, and excessive deposition of extracellular matrix, which in turn enhance the risk of lung fibrosis and graft rejection. We also found exclusive expression of HLA-DQB1, JCHAIN, SAP18, FUCA1, MZB1, G3BP2, and BTF3 in CLAD cases, indicating they could be specific biomarkers of CLAD. CONCLUSIONS: This study identifies distinct proteomes that are linked to CLAD development and consequently may be a useful indicator for identifying LTx patients at higher risk of CLAD.