• Jing Zhai, Michael Insel, Kenneth J Addison, Debra A Stern, William Pederson, Alane Dy, Joselyn Rojas-Quintero, Caroline A Owen, Duane L Sherrill, Wayne Morgan, Anne L Wright, Marilyn Halonen, Fernando D Martinez, Monica Kraft, Stefano Guerra, and Julie G Ledford.
• 1 Asthma and Airway Disease Research Center.
• Am. J. Respir. Crit. Care Med. 2019 Feb 1; 199 (3): 302312302-312.

RationaleCC16 (club cell secretory protein-16), 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.ObjectivesTo determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions.MethodsUsing human data from the birth cohort of the Tucson Children's Respiratory Study, 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 wild-type and CC16-/- mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway.Measurements And Main ResultsWe observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16-/- mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16-/- mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness.ConclusionsOur 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.

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