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Club Cells, Their Secretory Protein, and COPDClub Cells in COPD FREE TO VIEW

Peter J. Barnes, DM, DSc, Master FCCP
Author and Funding Information

From the Airway Disease Section, National Heart and Lung Institute, Imperial College London.

CORRESPONDENCE TO: Peter J. Barnes, DM, DSc, Master FCCP, Airway Disease Section, National Heart and Lung Institute, Dovehouse St, London, SW3 6LY, England; e-mail: p.j.barnes@imperial.ac.uk


FINANCIAL/NONFINANCIAL DISCLOSURES: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(6):1447-1448. doi:10.1378/chest.14-3171
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Club cells are nonciliated epithelial cells found mainly in bronchioles as well as basal cells found in large airways. They have been ascribed several protective roles, including airway repair after injury, secretion of antiinflammatory and immunomodulatory proteins, and detoxification.1 The study by Gamez et al2 in this issue of CHEST (see page 1467) reports a reduction in the number of club cells in bronchial biopsy specimens from patients with COPD compared with matched normal smokers, suggesting that these cells may normally have a protective role against the development of airway obstruction. Ablation of club cells in transgenic mice results in squamous metaplasia of the airways with impaired epithelial cell regeneration and peribronchiolar fibrosis reminiscent of the changes seen in COPD airways.3

The major secretory product of club cells is club cell secretory protein (CSSP [also known as CC-16, CC-10, uteroglobin, and secretoglobin family 1A member 1]), which is a homodimeric 10-kDa protein that has immunomodulatory effects and inhibits phospholipase A2, thus inhibiting the synthesis of eicosanoids. CCSP knockout mice show an increased lung inflammatory response to inhaled lipopolysaccharide, with increased neutrophils and tumor necrosis factor-α secretion.4 Furthermore, CCSP inhibits the release of oxidants from activated equine neutrophils and enhances their phagocytic ability.5 CCSP suppresses the secretion of CXCL8 and MUC5AC stimulated by lipopolysaccharide in cultured human airway epithelial cells by inhibiting the phosphorylation of nuclear factor-κB and extracellular regulated kinase.6 However, CCSP knockout mice do not appear to be more susceptible to the development of emphysema after long-term exposure to cigarettes, although murine club cells may differ from those in human airways.7 CCSP is detectable in the circulation, its concentration is reduced in patients with COPD, and it appears to be somewhat more reduced in patients with more rapid disease progression, although the magnitude of this difference is small and the variability between patients means this is unlikely to be a useful biomarker of disease progression.7 A reduction in CCSP-positive cells has previously been reported in peripheral and central airways in resected lung tissue from patients with COPD and is correlated with reduced FEV1 and neutrophil inflammation in large airways.8 Gamez et al2 show that CCSP secretion is reduced in cultured bronchial epithelial cells from patients with COPD, which also release more CXCL8.2 Furthermore, recombinant human CCSP (rhCCSP) restores the increase in CXCL8 induced by exposure to cigarette smoke-conditioned medium back to normal. In addition to CCSP, club cells also secrete a secretory component of IgA, which is also reduced in COPD and may be a factor in bacterial colonization of the airways in COPD.8 Several cytochrome P (CYP) 450 enzymes localize to club cells and play an important role in detoxifying inhaled xenobiotics.9 Club cells also secrete surfactants that may play a role in stabilizing small airways.

The mechanisms for the loss of club cells and CCSP in COPD are not clear. Some evidence for an association with polymorphisms of the gene encoding CCSP (Scgb1A1) are associated with COPD,10 but reduced numbers of club cells are more likely due to cigarette smoke exposure in susceptible individuals. Club cells are susceptible to selective damage by certain chemicals metabolized to toxic metabolites by CYP450 enzymes. For example, naphthalene is metabolized by CYP2F2, which is highly and uniquely expressed in club cells, resulting in selective damage and depletion of these cells from the airways.11 Toxins in cigarette smoke are likely to have a similar deleterious effect on club cells. However, club cell numbers are also reduced in other lung diseases, including asthma12 and bronchiolitis obliterans following lung transplantation,13 suggesting that several mechanisms cause the depletion of these cells.

Reduced numbers of club cells and reduced CCSP in peripheral and central airways of patients with COPD may represent an important mechanism of disease, resulting in impaired epithelial repair and peribronchiolar fibrosis with enhanced local inflammation and increased mucus secretion. This suggests that treatment with CCSP may have therapeutic potential in patients with COPD. rhCCSP has already been administered intratracheally as a single dose to premature infants with respiratory distress syndrome, with evidence of reduced inflammation in tracheal aspirates and no safety issues.14 rhCCSP is stable and easy to synthesize, and its plasma half-life is > 10 h, suggesting that daily administration by nebulization or dry powder should be possible. Repeated daily dosing of rhCCSP may be practical in COPD, although no clinical trials appear to be ongoing. New treatments for COPD that deal with the underlying disease process are urgently needed.15

References

Hiemstra PS, Bourdin A. Club cells, CC10 and self-control at the epithelial surface. Eur Respir J. 2014;44(4):831-832. [CrossRef] [PubMed]
 
Gamez AS, Gras D, Petit A, et al. Supplementing defect in club cell secretory protein attenuates airway inflammation in COPD. Chest. 2015;147(6):1467-1476.
 
Perl AK, Riethmacher D, Whitsett JA. Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis. Am J Respir Crit Care Med. 2011;183(4):511-521. [CrossRef] [PubMed]
 
Snyder JC, Reynolds SD, Hollingsworth JW, Li Z, Kaminski N, Stripp BR. Clara cells attenuate the inflammatory response through regulation of macrophage behavior. Am J Respir Cell Mol Biol. 2010;42(2):161-171. [CrossRef] [PubMed]
 
Katavolos P, Ackerley CA, Clark ME, Bienzle D. Clara cell secretory protein increases phagocytic and decreases oxidative activity of neutrophils. Vet Immunol Immunopathol. 2011;139(1):1-9. [CrossRef] [PubMed]
 
Tokita E, Tanabe T, Asano K, Suzaki H, Rubin BK. Club cell 10-kDa protein attenuates airway mucus hypersecretion and inflammation. Eur Respir J. 2014;44(4):1002-1010. [CrossRef] [PubMed]
 
Park HY, Churg A, Wright JL, et al. Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188(12):1413-1419. [CrossRef] [PubMed]
 
Pilette C, Godding V, Kiss R, et al. Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(1):185-194. [CrossRef] [PubMed]
 
Hukkanen J, Pelkonen O, Hakkola J, Raunio H. Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit Rev Toxicol. 2002;32(5):391-411. [CrossRef] [PubMed]
 
Kim DK, Cho MH, Hersh CP, et al; ECLIPSE, ICGN, and COPDGene Investigators. Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(12):1238-1247. [CrossRef] [PubMed]
 
Stripp BR, Maxson K, Mera R, Singh G. Plasticity of airway cell proliferation and gene expression after acute naphthalene injury. Am J Physiol. 1995;269(6 pt 1):L791-L799. [PubMed]
 
Shijubo N, Itoh Y, Yamaguchi T, et al. Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med. 1999;160(3):930-933. [CrossRef] [PubMed]
 
Kelly FL, Kennedy VE, Jain R, et al. Epithelial Clara cell injury occurs in bronchiolitis obliterans syndrome after human lung transplantation. Am J Transplant. 2012;12(11):3076-3084. [CrossRef] [PubMed]
 
Levine CR, Gewolb IH, Allen K, et al. The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res. 2005;58(1):15-21. [CrossRef] [PubMed]
 
Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov. 2013;12(7):543-559. [CrossRef] [PubMed]
 

Figures

Tables

References

Hiemstra PS, Bourdin A. Club cells, CC10 and self-control at the epithelial surface. Eur Respir J. 2014;44(4):831-832. [CrossRef] [PubMed]
 
Gamez AS, Gras D, Petit A, et al. Supplementing defect in club cell secretory protein attenuates airway inflammation in COPD. Chest. 2015;147(6):1467-1476.
 
Perl AK, Riethmacher D, Whitsett JA. Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis. Am J Respir Crit Care Med. 2011;183(4):511-521. [CrossRef] [PubMed]
 
Snyder JC, Reynolds SD, Hollingsworth JW, Li Z, Kaminski N, Stripp BR. Clara cells attenuate the inflammatory response through regulation of macrophage behavior. Am J Respir Cell Mol Biol. 2010;42(2):161-171. [CrossRef] [PubMed]
 
Katavolos P, Ackerley CA, Clark ME, Bienzle D. Clara cell secretory protein increases phagocytic and decreases oxidative activity of neutrophils. Vet Immunol Immunopathol. 2011;139(1):1-9. [CrossRef] [PubMed]
 
Tokita E, Tanabe T, Asano K, Suzaki H, Rubin BK. Club cell 10-kDa protein attenuates airway mucus hypersecretion and inflammation. Eur Respir J. 2014;44(4):1002-1010. [CrossRef] [PubMed]
 
Park HY, Churg A, Wright JL, et al. Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188(12):1413-1419. [CrossRef] [PubMed]
 
Pilette C, Godding V, Kiss R, et al. Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163(1):185-194. [CrossRef] [PubMed]
 
Hukkanen J, Pelkonen O, Hakkola J, Raunio H. Expression and regulation of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes in human lung. Crit Rev Toxicol. 2002;32(5):391-411. [CrossRef] [PubMed]
 
Kim DK, Cho MH, Hersh CP, et al; ECLIPSE, ICGN, and COPDGene Investigators. Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;186(12):1238-1247. [CrossRef] [PubMed]
 
Stripp BR, Maxson K, Mera R, Singh G. Plasticity of airway cell proliferation and gene expression after acute naphthalene injury. Am J Physiol. 1995;269(6 pt 1):L791-L799. [PubMed]
 
Shijubo N, Itoh Y, Yamaguchi T, et al. Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med. 1999;160(3):930-933. [CrossRef] [PubMed]
 
Kelly FL, Kennedy VE, Jain R, et al. Epithelial Clara cell injury occurs in bronchiolitis obliterans syndrome after human lung transplantation. Am J Transplant. 2012;12(11):3076-3084. [CrossRef] [PubMed]
 
Levine CR, Gewolb IH, Allen K, et al. The safety, pharmacokinetics, and anti-inflammatory effects of intratracheal recombinant human Clara cell protein in premature infants with respiratory distress syndrome. Pediatr Res. 2005;58(1):15-21. [CrossRef] [PubMed]
 
Barnes PJ. New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov. 2013;12(7):543-559. [CrossRef] [PubMed]
 
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