Abstract Rationale Club cell secretory protein (CC16), encoded by SCGB1A1, is secreted by non-ciliated airway epithelial cells and exerts anti-inflammatory and epithelial-protective functions. Decreased CC16 levels have been associated with asthma, but it remains unclear which airway compartment most accurately reflects disease activities and phenotypes. This study compared CC16 mRNA expression across four airway sample types—bronchial brushings, bronchial biopsies, sputum, and nasal brushings—to determine which best mirrors asthma burden and molecular inflammatory signatures. Methods Data from 206 participants in the U-BIOPRED adult cohort (54 healthy controls, 48 mild-to-moderate asthma, 104 severe asthma) were analyzed. CC16 mRNA expression was measured in the four airway sample types using microarray. Associations with asthma severity, symptom scores, exacerbations, lung function, blood/sputum cell counts, cytokine-induced gene signatures (IL-5, IL-13, IL-6-trans-signaling, IL-17), quantitative pathological metrics, and eicosanoid metabolites were evaluated. Group differences were examined by Dunn’s test with Bonferroni-Holm correction. Associations between CC16 mRNA expression and clinical, molecular, and biochemical parameters were examined using logistic and linear regression analyses, including both univariate and multivariate models adjusted for age, gender, race, and BMI. Results Among four airway samples, CC16 mRNA expression in bronchial brushings showed the most consistent inverse associations with asthma presence, asthma severity, worse symptom burden (ACQ, AQLQ, SNOT), and exacerbations. Bronchial epithelial CC16 mRNA also inversely correlated with blood and sputum eosinophils, neutrophils, and enrichment scores for IL-5, IL-13, and IL-6 trans-signaling gene signatures. These associations remained significant after adjusting with age, gender, race, and BMI. CC16 mRNA expression in bronchial biopsy, sputum, and nasal samples exhibited similar but progressively weaker trends in this order. Nasal CC16 mRNA expression was specifically correlated with FeNO but not with neutrophil-related indices. Conclusions CC16 mRNA expression in the bronchial epithelium provides the most sensitive molecular readout of asthma burden and both type 2 and non-type 2 inflammatory activity among airway sample types. These findings establish bronchial brush CC16 mRNA as a robust biomarker of epithelial health and disease heterogeneity in asthma, highlighting that CC16 expression in the lower airways, where asthma pathology originates, most accurately reflects the underlying disease activity and emphasizes the value of lower airway sampling for mechanistic and translational studies. This abstract is funded by: National Institute of Health grant NIAID U19125357, The European Union’s Seventh Framework Programme (FP7/2007-2013), Innovative Medicines Initiative Joint Undertaking (grant115010).
Kimura et al. (Fri,) studied this question.