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

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

Author information

1
Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA These authors contributed equally to this manuscript.
2
Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Lovelace Respiratory Research Institute, Albuquerque, NM, USA Pulmonary Division, University of Parma, Parma, Italy These authors contributed equally to this manuscript.
3
Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
4
Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
5
Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
6
Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
7
Clarassance Inc., Rockville, MD, USA.
8
Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Lovelace Respiratory Research Institute, Albuquerque, NM, USA cowen@rics.bwh.harvard.edu.

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.

PMID:
25700379
PMCID:
PMC4451404
DOI:
10.1183/09031936.00134214
[Indexed for MEDLINE]
Free PMC Article
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