title: Protective role for club cell secretory protein-16 (CC16) in the development of COPD.
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.
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA These authors contributed equally to this manuscript.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Laucho-Contreras
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Polverino
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Kushagra
authors.initials: K
authors.lastname: Gupta
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Taylor
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Emer
authors.initials: E
authors.lastname: Kelly
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Pinto-Plata
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Divo
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Naveed
authors.initials: N
authors.lastname: Ashfaq
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Petersen
authors.affiliation: Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Stripp
authors.affiliation: Clarassance Inc., Rockville, MD, USA.
authors.forename: Aprile L
authors.initials: AL
authors.lastname: Pilon
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.affiliation: Pulmonary Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA Lovelace Respiratory Research Institute, Albuquerque, NM, USA.
authors.forename: Bartolome R
authors.initials: BR
authors.lastname: Celli
authors.affiliation: 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.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D017209:Apoptosis; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D055879:Gene Knock-In Techniques; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D055271:Mucin 5AC / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress; D054497:Phospholipases A2, Secretory / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000378:metabolism; D012129:Respiratory Function Tests; D012906:Smoke; D012907:Smoking / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014026:Nicotiana; D014598:Uteroglobin / Q000235:genetics* / Q000378:metabolism*
chemical_list: C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D016328:NF-kappa B; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D012906:Smoke; D017392:Thiobarbituric Acid Reactive Substances; D003577:Cytochrome P-450 Enzyme System; D014598:Uteroglobin; C110333:Cyp2f2 protein, mouse; D054497:Phospholipases A2, Secretory; C505409:Casp3 protein, mouse; D053148:Caspase 3