Club cell proportion and transcriptomic profile are altered in allograft dysfunction in lung transplant recipients

<bold>Rationale:</bold> Chronic lung allograft dysfunction (CLAD) limits survival in lung transplant recipients and may be detected early as acute lung allograft dysfunction (ALAD). We hypothesized that club cell dysfunction is a mechanistic driver of CLAD and evaluated cell composition and transcriptome changes in ALAD and CLAD. <bold>Methods:</bold> Bronchoscopic small airway brushings of lung transplant recipients (5 stable, 5 CLAD or ALAD) were subjected to single-cell RNA-sequencing. <bold>Results:</bold> Transcriptomic analysis identified epithelial and immune cells in the small airway brushings. Focused evaluation of epithelial cells revealed clusters of basal, club, ciliated, goblet, ionocyte, and deuterosomal cells. Club cells were defined by the expression of SCGB1A1 (club cell secretory protein). We observed an increase in proportion of club cells among all epithelial cells in ALAD/CLAD, but the expression level of SCGB1A1 was lower in club cells in ALAD/CLAD compared to stable. Comparison of club cell transcriptional differences showed that MHC genes and mucins were upregulated in ALAD/CLAD <bold>(Figure 1)</bold>. <bold>Conclusion:</bold> Reduced expression of CCSP in club cells, rather than lower numbers of club cells, is a feature of lung allograft dysfunction. These changes may indicate abnormal club cell differentiation in response to inflammation and injury. <fig><object-id>erjor;11/suppl_15/OP1/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>