Club cell secretory protein deficiency leads to altered lung
function

RATIONALE: Club cell secretory protein-16 (CC16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases. OBJECTIVE: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions. METHODS AND MEASUREMENTS: Using human data from the birth cohort of the Tucson Children's Respiratory Study (TCRS), we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In WT and CC16-/- mice, we set out to comprehensively examine pulmonary physiology, inflammation and remodeling in the na{"\i}ve airway. MAIN RESULTS: We observed that TCRS participants in the lowest tertile of serum CC16 have significant deficits in their lung function and enhanced airway hyperresponsiveness (AHR) to methacholine challenge from 11 years throughout young adult life. Similarly, CC16-/- mice had significant deficits in lung function and enhanced AHR to methacholine as compared to WT mice, which were independent of inflammation and mucin production. As compared to WT mice, CC16-/- mice had significantly elevated gene expression of pro-collagen type I, pro-collagen type III and alpha-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness. CONCLUSIONS: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.