Club Cell Protein 16 (CC16) Augmentation: A Potential Disease-modifying Approach for Chronic Obstructive Pulmonary Disease (COPD)

ABSTRACT

Introduction: Club cell protein 16 (CC16) is the most abundant protein in bronchoalveolar lavage fluid. CC16 has anti-inflammatory properties in smoke-exposed lungs, and chronic obstructive pulmonary disease (COPD) is associated with CC16 deficiency. Herein, we explored whether CC16 is a therapeutic target for COPD.

Areas Covered: We reviewed the literature on the factors that regulate airway CC16 expression, its biologic functions and its protective activities in smoke-exposed lungs using PUBMED searches. We generated hypotheses on the mechanisms by which CC16 limits COPD development, and discuss its potential as a new therapeutic approach for COPD.

Expert Opinion: CC16 plasma and lung levels are reduced in smokers without airflow obstruction and COPD patients. In COPD patients, airway CC16 expression is inversely correlated with severity of airflow obstruction. CC16 deficiency increases smoke-induced lung pathologies in mice by its effects on epithelial cells, leukocytes, and fibroblasts. Experimental augmentation of CC16 levels using recombinant CC16 in cell culture systems, plasmid and adenoviral-mediated over-expression of CC16 in epithelial cells or smoke-exposed murine airways reduces inflammation and cellular injury. Additional studies are necessary to assess the efficacy of therapies aimed at restoring airway CC16 levels as a new disease-modifying therapy for COPD patients.

KEYWORDS:

• Bronchoalveolar lavage fluid
• CC10
• CC16
• chronic bronchitis
• Club cells
• COPD
• emphysema
• formyl peptide receptor-2
• lipoxin A₄
• lung inflammation
• nuclear factor kappa B
• phospholipase A₂
• recombinant therapy
• serum amyloid A
• secretoglobin 1A1
• small airway remodeling
• toll-like receptor
• uteroglobin

Article highlights

• Club cell protein-16 (CC16) is a major product of Club cells and it is a marker of epithelial airway injury.

• COPD is associated with CC16 deficiency as CC16 BALF and serum levels are lower in COPD patients versus smokers without COPD, and lower in smokers without COPD than healthy nonsmoker controls.

• Low serum CC16 levels are linked to rapid rate of decline in lung function in COPD patients and to the chronic bronchitis COPD phenotype.

• CC16 protects lungs from cigarette smoke (CS)-induced pulmonary inflammation and injury. CC16 deficiency in mice leads to greater CS-induced pulmonary inflammation, bronchial and alveolar epithelial cell apoptosis, mucus metaplasia, increases in lung compliance, airspace enlargement, and small airway fibrosis.

• Adenoviral vector-mediated overexpression of CC16 reduces release of pro-inflammatory mediators by activated epithelial cell cultures in vitro, and reduces pulmonary inflammation, lung epithelial cell apoptosis, and mucus metaplasia in the lungs of smoke-exposed mice.

• Adding recombinant CC16 (rCC16) to activated epithelial cell cultures decreases their release of pro-inflammatory mediators and expression of mucins.

• The beneficial effects of delivering or overexpressing CC16 in cells or smoke-exposed murine lungs are associated with reduced nuclear translocation of the pro-inflammatory transcription factor, NFκB.

• Currently, there are no published studies determining whether chronic delivery of rCC16 in COPD patients is safe and reduces CS-induced lung inflammation or injury.

• CC16 augmentation approaches including delivering rCC16 to the lungs of COPD patients could represent a first-in-class disease-modifying therapy for COPD by boosting key anti-inflammatory pathways that are downregulated in COPD lungs.

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Financial and competing interests disclosure

The authors were supported by the United States Public Health Service; the National Institutes of Health under National Heart, Lung, and Blood Institute (grant numbers HL063137, HL086814, HL111835, PO1 HL105339, P01 HL114501, and AI111475-01); the Flight Attendants Medical Research Institute (grant numbers CIA123046 and YFEL141004); and the Brigham and Women’s Hospital-Lovelace Respiratory Research Institute Consortium. Aprile Pilon is co-founder, CEO and a major shareholder of Therabron Therapeutics, a biotechnology company dedicated to developing human recombinant CC16 protein as a drug for treating human lung diseases. Aprile Pilon also has several patents issued (publication numbers: US6255281 B1; US7122344 B2; US7846899 B2; US8470767 B2) and pending (application numbers: US 13/501,908; US 12/945,622; US 12/637,573) in this area. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.