RATIONALE: CC16 is a protein mainly produced by non-ciliated bronchial epithelial cells (BEC) that participates in host defense. Reduced CC16 protein levels in bronchoalveolar lavage and serum are associated with asthma susceptibility.
OBJECTIVES: Few studies have investigated the relationship of CC16 and asthma progression, and none has focused on BEC. In this study, we sought to determine if CC16 mRNA expression levels in BEC are associated with asthma severity.
METHODS: Association analyses between CC16 mRNA expression levels in BEC (242 asthmatics and 69 controls) and asthma-related phenotypes in the Severe Asthma Research Program (SARP) were performed using a generalized linear model.
MEASUREMENTS AND MAIN RESULTS: Low CC16 mRNA expression levels in BEC were significantly associated with asthma susceptibility and asthma severity, high systemic corticosteroids use, high retrospective and prospective asthma exacerbations, and low pulmonary function. Low CC16 mRNA expression levels were significantly associated with high T2 inflammation biomarkers (fractional exhaled nitric oxide (FeNO) and sputum eosinophils). CC16 mRNA expression levels were negatively correlated with expression levels of Th2 genes (IL1RL1, POSTN, SERPINB2, CLCA1, NOS2, and MUC5AC), and positively correlated with expression levels of Th1 and inflammation genes (IL12A and MUC5B). A combination of two non-T2 biomarkers (CC16 and IL-6) revealed four asthma endotypes with different characteristics of T2 inflammation, obesity, and asthma severity.
CONCLUSIONS: Our findings indicate that low CC16 mRNA expression levels in BEC are associated with asthma susceptibility, severity, and exacerbations, partially through immunomodulation of T2 inflammation. CC16 is a potential non-T2 biomarker for asthma development and progression.