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

Eur Respir J. 2015 Jun;45(6):1544-56. doi: 10.1183/09031936.00134214. Epub 2015 Feb 19.

Abstract

Club cell secretory protein-16 (CC16) is the major secreted product of airway club cells, but its role in the pathogenesis of chronic obstructive pulmonary disease (COPD) is unclear. We measured CC16 airway expression in humans with and without COPD and CC16 function in a cigarette smoke (CS)-induced COPD murine model. Airway CC16 expression was measured in COPD patients, smokers without COPD and non-smokers. We exposed wildtype (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 mucin 5AC (MUC5AC) expression, small airway remodelling and pulmonary function. 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 remodelling, pulmonary inflammation, alveolar cell apoptosis, airway MUC5AC expression, and more compliant lungs than WT mice. These changes were associated with increased nuclear factor-κB (NF-κB) activation in CC16(-/-) lungs. CS-induced acute pulmonary changes were reversed by adenoviral-mediated over-expression of CC16. CC16 protects lungs from CS-induced injury by reducing lung NF-κB activation. CS-induced airway CC16 deficiency increases CS-induced pulmonary inflammation and injury and likely contributes to the pathogenesis of COPD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling
  • Animals
  • Apoptosis
  • Case-Control Studies
  • Caspase 3 / metabolism
  • Cytochrome P-450 Enzyme System / metabolism
  • Gene Knock-In Techniques
  • Humans
  • Lung / metabolism*
  • Lung / physiopathology
  • Mice
  • Mice, Knockout
  • Mucin 5AC / metabolism
  • NF-kappa B / metabolism*
  • Oxidative Stress
  • Phospholipases A2, Secretory / metabolism
  • Pulmonary Alveoli / cytology
  • Pulmonary Disease, Chronic Obstructive / metabolism*
  • Pulmonary Emphysema / metabolism
  • Respiratory Function Tests
  • Smoke*
  • Smoking / metabolism*
  • Thiobarbituric Acid Reactive Substances / metabolism
  • Tobacco*
  • Uteroglobin / genetics*
  • Uteroglobin / metabolism*

Substances

  • Muc5ac protein, mouse
  • Mucin 5AC
  • NF-kappa B
  • SCGB1A1 protein, human
  • Scgb1a1 protein, mouse
  • Smoke
  • Thiobarbituric Acid Reactive Substances
  • Cytochrome P-450 Enzyme System
  • Uteroglobin
  • Cyp2f2 protein, mouse
  • Phospholipases A2, Secretory
  • Casp3 protein, mouse
  • Caspase 3