197 Unveiling the Role of Gut As a Player in Lung Inflammation Using Novel Collaborative Cross Mice with ΔF508-Cftr Mutation

function.Surgically resected sinonasal tissues and explanted donor lungs were used to validate findings.Results: scRNA-seq analysis completed for 9 healthy subjects and 10 PwCF revealed persistent differences between PwCF receiving HEMT and healthy controls.Substantial neutrophilic inflammation was prominent in the CF sinonasal mucosa, indicated by excess neutrophils with CF-specific programming and high pro-inflammatory gene expression in virtually all epithelial cell types.The CF epithelium continues to exhibit evidence of remodeling based on gene expression signatures consistent with immature ciliated cells and mucous and squamous cell metaplasia.The underlying CF basal cell stem pool contained a different proportion of proliferating, resting, and differentiating cells than the healthy samples.Trajectory analysis suggests that cellular differentiation pathways remain altered in CF, potentially because of an increase in injury repair.Computational prediction of cell-cell signaling relationships revealed changes in Notch, Wnt, and other signaling pathways that control epithelial differentiation.Evidence of aberrant cell signaling and epithelial cells with altered structure and programming were also detectable in histological sections of sinonasal tissue.ALI cultures derived from CF sinonasal airway epithelial cells isolated after 6 months of HEMT remained detectably different from healthy controls, with less differentiation capacity and barrier function.Conclusions: Despite considerable clinical improvements at 6 months, airway epithelial inflammation and dysfunction are not fully rectified when HEMT is initiated in adults with existing airway disease.Unraveling the molecular mechanisms driving these responses will have implications for the long-term use of HEMT, especially in an aging population of PwCF.