Early BAL microRNA Signatures Delineate Biological Trajectories Towards CLAD After Lung Transplantation

Chronic lung allograft dysfunction (CLAD) remains the principal limitation to long-term survival after lung transplantation (LT). Early molecular alterations within the graft may precede clinically overt functional decline, but their biological significance remains incompletely defined. In this single-center exploratory pilot study, 16 bilateral lung transplant recipients underwent bronchoalveolar lavage (BAL) sampling at 7 days, 15 days, and 3 months post-transplantation. BAL-derived microRNA (miRNA) profiles were analyzed longitudinally and correlated with long-term clinical outcomes, including CLAD development and phenotypic classification into bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS), over extended follow-up (mean 98 months). Distinct early miRNA signatures were detectable within the first weeks after transplantation and were associated with divergent long-term clinical trajectories. Specific miRNAs, namely let-7e-5p and miR-30d-3p, were associated with subsequent CLAD, whereas differential expression patterns distinguished trajectories toward BOS or RAS. Enrichment analyses highlighted networks related to innate immune activation, hypoxia, tissue remodeling, and PI3K-mTOR signaling. Notably, the occurrence of acute rejection did not differ significantly between patients who developed CLAD and those who remained stable. These findings, although preliminary, suggest that early BAL-derived miRNA profiles may reflect biologically distinct graft states associated with long-term CLAD phenotypes.