Protective role for club cell secretory protein-16 (CC16) in the development of COPD

Abstract

Rationale Club cell secretory protein-16 (CC16) is the major secreted product of airway Club cells, but its role in the pathogenesis of COPD is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD mice model. Methods Airway CC16 expression was measured in COPD patients, smokers without COPD, and non-smokers. We exposed wild-type (WT) and CC16-/- mice to CS or air for up to 6 months, and measured airway CC16 expression, pulmonary inflammation, alveolar septal cell apoptosis, airspace enlargement, airway MUC5AC expression, small airway remodeling, and pulmonary function. Results Smokers and COPD patients had reduced airway CC16 immunostaining that decreased with increasing COPD severity. Exposing mice to CS reduced airway CC16 expression. CC16-/- mice had greater CS-induced emphysema, airway remodeling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NFκB) activation in CC16-/- lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. Conclusions CC16 protects lungs from CS-induced injury by reducing lung NFκB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.

Low plasma CC16 levels in smokers are associated with a higher risk for chronic bronchitis

“…In a logistic regression model, adjusted for age, sex, Hispanic ethnicity, baseline BMI, pack years, current smoking at baseline and baseline per cent predicted FEV1, CC16 showed a negative association with COPD (OR 0.71, p=0.01; n=313/1210). This is also consistent with our recent findings in mice and humans [5].…”

“…Serum CC16 levels are low in cigarette smokers [3] and increase following smoking cessation [4], but patients with chronic obstructive pulmonary disease (COPD) show progressive decrease in CC16 with disease severity [5]. Thus, although the association between circulating levels of CC16 and airflow obstruction is accepted, the association between circulating CC16 and chronic bronchitis, and whether a link in association exists between circulating CC16 levels, lung function decline and chronic bronchitis have not been shown.…”

Club cells and CC16: another “smoking gun”? (With potential bullets against COPD)

“…Serum CC16 level has been shown as a potential biomarker of accelerated lung function decline in a very large cohort [7]. CC16 polymorphism and local deficiency on the one hand, and a decreased number of club cells on the other hand, were reported as features of COPD [8,9], as confirmed by LAUCHO-CONTRERAS et al [10] in the current issue of the European Respiratory Journal. In previous studies, exogenous CC16 showed pharmacological properties that could decrease excess airway inflammation and mucus production in ex vivo models [11][12][13].…”

“…The paper by LAUCHO-CONTRERAS et al [10] has reported novel and important observations of knockout CC16 mice exposed to 6 months of smoking. They not only observed an increased susceptibility of the knockout animals to emphysema and peribronchiolar fibrosis, but also unravelled potential mechanisms of action of CC16 involved in COPD development.…”

Diagnostic and prognostic values of Club cell protein 16 (CC16) in critical care patients with acute respiratory distress syndrome

“…While previous studies have demonstrated a relatively stable median CC16 value in normal controls (5‐7 ng/mL),12, 13 the median CC16 value of non‐ARDS patients in this study appeared to be higher (24.13±12.32 ng/mL). Some cases from the non‐ARDS patient group had developed pulmonary diseases such as pneumonia, which may have caused an elevated production of CC16 18. The compromised renal function indicated by an increase of Scr in some non‐ARDS patients may be another reason accounting for the difference in the CC16 levels since a decreased glomerular filtration rate retards the clearance of CC16 19…”