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Published in: BMC Pulmonary Medicine 1/2018

Open Access 01-12-2018 | Research article

CC16 levels correlate with cigarette smoke exposure in bronchial epithelial cells and with lung function decline in smokers

Authors: David Chi-Leung Lam, Hoi-Hin Kwok, Wai-Cho Yu, Fanny Wai-San Ko, Cheuk-Yin Tam, Arthur Chun-Wing Lau, Daniel Yee-Tak Fong, Mary Sau-Man Ip

Published in: BMC Pulmonary Medicine | Issue 1/2018

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Abstract

Background

Club cell protein-16 (CC16) expression has been associated with smoking-related lung function decline. The study hypothesis was that CC16 expression in both serum and bronchial epithelium is associated with lung function decline in smokers, and exposure to cigarette smoke will lead to reduction in CC16 expression in bronchial epithelial cells.

Methods

In a cohort of community-based male Chinese subjects recruited for lung function test in 2000, we reassessed their lung function ten years later and measured serum levels of CC16. CC16 expression was further assayed in bronchial epithelium from endobronchial biopsies taken from an independent cohort of subjects undergoing autofluorescence bronchoscopy, and tested for correlation between CC16 immunostaining intensity and lung function. In an in-vitro model, bronchial epithelial cells were exposed to cigarette smoke extract (CSE), and the expression levels of CC16 were measured in bronchial epithelial cells before and after exposure to CSE.

Results

There was a significant association between FEV1 decline and serum CC16 levels in smokers. Expression of CC16 in bronchial epithelium showed significant correlation with FEV1/FVC. Bronchial epithelial cells showed significant decrease in CC16 expression after exposure to CSE, followed by a subsequent rise in CC16 expression upon removal of CSE.

Conclusions

Results of these clinical and laboratory investigations suggested that low serum CC16 was associated with smoking-related decline in lung function, demonstrated the first time in a Chinese cohort. The data also lend support to the putative role of CC16 in protection against smoking-related bronchial epithelial damage.
(Abstract word count: 243)

US clinical trial registry

NCT01185652, first posted 20 August, 2010.
Literature
2.
go back to reference Drummond MB, Hansel NN, Connett JE, Scanlon PD, Tashkin DP, Wise RA. Spirometric predictors of lung function decline and mortality in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(12):1301–6.CrossRefPubMedPubMedCentral Drummond MB, Hansel NN, Connett JE, Scanlon PD, Tashkin DP, Wise RA. Spirometric predictors of lung function decline and mortality in early chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(12):1301–6.CrossRefPubMedPubMedCentral
3.
go back to reference Global Strategy for the Diagnosis, Management and prevention of COPD, global initiative for chronic obstructive lung disease (GOLD) 2016.2016 Available from: http://wwwgoldcopdorg/ . Global Strategy for the Diagnosis, Management and prevention of COPD, global initiative for chronic obstructive lung disease (GOLD) 2016.2016 Available from: http://​wwwgoldcopdorg/​ .
4.
go back to reference Dickens JA, Lomas DA. CC-16 as a biomarker in chronic obstructive pulmonary disease. COPD. 2012;9(5):574–5.CrossRefPubMed Dickens JA, Lomas DA. CC-16 as a biomarker in chronic obstructive pulmonary disease. COPD. 2012;9(5):574–5.CrossRefPubMed
5.
go back to reference Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065–72.CrossRefPubMed Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185(10):1065–72.CrossRefPubMed
6.
go back to reference Garcia-Rio F, Miravitlles M, Soriano JB, Munoz L, Duran-Tauleria E, Sanchez G, Sobradillo V, Ancochea J, Committee E-SS. Systemic inflammation in chronic obstructive pulmonary disease: a population-based study. Respir Res. 2010;11:63.CrossRefPubMedPubMedCentral Garcia-Rio F, Miravitlles M, Soriano JB, Munoz L, Duran-Tauleria E, Sanchez G, Sobradillo V, Ancochea J, Committee E-SS. Systemic inflammation in chronic obstructive pulmonary disease: a population-based study. Respir Res. 2010;11:63.CrossRefPubMedPubMedCentral
7.
go back to reference Knabe L, Fort A, Chanez P, Bourdin A. Club cells and CC16: another “smoking gun”? (with potential bullets against COPD). Eur Respir J. 2015;45(6):1519–20.CrossRefPubMed Knabe L, Fort A, Chanez P, Bourdin A. Club cells and CC16: another “smoking gun”? (with potential bullets against COPD). Eur Respir J. 2015;45(6):1519–20.CrossRefPubMed
8.
go back to reference Guerra S, Halonen M, Vasquez MM, Spangenberg A, Stern DA, Morgan WJ, Wright AL, Lavi I, Tares L, Carsin AE, et al. Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. Lancet Respir Med. 2015;3(8):613–20.CrossRefPubMedPubMedCentral Guerra S, Halonen M, Vasquez MM, Spangenberg A, Stern DA, Morgan WJ, Wright AL, Lavi I, Tares L, Carsin AE, et al. Relation between circulating CC16 concentrations, lung function, and development of chronic obstructive pulmonary disease across the lifespan: a prospective study. Lancet Respir Med. 2015;3(8):613–20.CrossRefPubMedPubMedCentral
9.
go back to reference Bernard A, Marchandise FX, Depelchin S, Lauwerys R, Sibille Y. Clara cell protein in serum and bronchoalveolar lavage. Eur Respir J. 1992;5(10):1231–8.PubMed Bernard A, Marchandise FX, Depelchin S, Lauwerys R, Sibille Y. Clara cell protein in serum and bronchoalveolar lavage. Eur Respir J. 1992;5(10):1231–8.PubMed
10.
go back to reference Broeckaert F, Clippe A, Knoops B, Hermans C, Bernard A. Clara cell secretory protein (CC16): features as a peripheral lung biomarker. Ann N Y Acad Sci. 2000;923:68–77.CrossRefPubMed Broeckaert F, Clippe A, Knoops B, Hermans C, Bernard A. Clara cell secretory protein (CC16): features as a peripheral lung biomarker. Ann N Y Acad Sci. 2000;923:68–77.CrossRefPubMed
11.
go back to reference Laucho-Contreras ME, Polverino F, Gupta K, Taylor KL, Kelly E, Pinto-Plata V, Divo M, Ashfaq N, Petersen H, Stripp B, et al. Protective role for club cell secretory protein-16 (CC16) in the development of COPD. Eur Respir J. 2015;45(6):1544–56.CrossRefPubMedPubMedCentral Laucho-Contreras ME, Polverino F, Gupta K, Taylor KL, Kelly E, Pinto-Plata V, Divo M, Ashfaq N, Petersen H, Stripp B, et al. Protective role for club cell secretory protein-16 (CC16) in the development of COPD. Eur Respir J. 2015;45(6):1544–56.CrossRefPubMedPubMedCentral
13.
go back to reference Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365(13):1184–92.CrossRefPubMed Vestbo J, Edwards LD, Scanlon PD, Yates JC, Agusti A, Bakke P, Calverley PM, Celli B, Coxson HO, Crim C, et al. Changes in forced expiratory volume in 1 second over time in COPD. N Engl J Med. 2011;365(13):1184–92.CrossRefPubMed
14.
go back to reference Park HY, Churg A, Wright JL, Li Y, Tam S, Man SF, Tashkin D, Wise RA, Connett JE, Sin DD. Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188(12):1413–9.CrossRefPubMedPubMedCentral Park HY, Churg A, Wright JL, Li Y, Tam S, Man SF, Tashkin D, Wise RA, Connett JE, Sin DD. Club cell protein 16 and disease progression in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2013;188(12):1413–9.CrossRefPubMedPubMedCentral
15.
go back to reference Lomas DA, Silverman EK, Edwards LD, Miller BE, Coxson HO, Tal-Singer R, Evaluation of CLtIPSEi: Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort. Thorax 2008, 63(12):1058–1063. Lomas DA, Silverman EK, Edwards LD, Miller BE, Coxson HO, Tal-Singer R, Evaluation of CLtIPSEi: Evaluation of serum CC-16 as a biomarker for COPD in the ECLIPSE cohort. Thorax 2008, 63(12):1058–1063.
16.
go back to reference Petersen H, Leng S, Belinsky SA, Miller BE, Tal-Singer R, Owen CA, Celli B, Tesfaigzi Y. Low plasma CC16 levels in smokers are associated with a higher risk for chronic bronchitis. Eur Respir J. 2015;46(5):1501–3.CrossRefPubMed Petersen H, Leng S, Belinsky SA, Miller BE, Tal-Singer R, Owen CA, Celli B, Tesfaigzi Y. Low plasma CC16 levels in smokers are associated with a higher risk for chronic bronchitis. Eur Respir J. 2015;46(5):1501–3.CrossRefPubMed
17.
go back to reference Laucho-Contreras ME, Polverino F, Tesfaigzi Y, Pilon A, Celli BR, Owen CA. Club cell protein 16 (CC16) augmentation: a potential disease-modifying approach for chronic obstructive pulmonary disease (COPD). Expert Opin Ther Targets. 2016;20(7):869–83. Laucho-Contreras ME, Polverino F, Tesfaigzi Y, Pilon A, Celli BR, Owen CA. Club cell protein 16 (CC16) augmentation: a potential disease-modifying approach for chronic obstructive pulmonary disease (COPD). Expert Opin Ther Targets. 2016;20(7):869–83.
18.
go back to reference Ip MS, Ko FW, Lau AC, Yu WC, Tang KS, Choo K, Chan-Yeung MM. Hong Kong thoracic S, American College of Chest P: updated spirometric reference values for adult Chinese in Hong Kong and implications on clinical utilization. Chest. 2006;129(2):384–92.CrossRefPubMed Ip MS, Ko FW, Lau AC, Yu WC, Tang KS, Choo K, Chan-Yeung MM. Hong Kong thoracic S, American College of Chest P: updated spirometric reference values for adult Chinese in Hong Kong and implications on clinical utilization. Chest. 2006;129(2):384–92.CrossRefPubMed
19.
go back to reference Lau AC, Ip MS, Lai CK, Choo KL, Tang KS, Yam LY, Chan-Yeung M. Variability of the prevalence of undiagnosed airflow obstruction in smokers using different diagnostic criteria. Chest. 2008;133(1):42–8.CrossRefPubMed Lau AC, Ip MS, Lai CK, Choo KL, Tang KS, Yam LY, Chan-Yeung M. Variability of the prevalence of undiagnosed airflow obstruction in smokers using different diagnostic criteria. Chest. 2008;133(1):42–8.CrossRefPubMed
20.
go back to reference Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.CrossRefPubMed Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, et al. Standardisation of spirometry. Eur Respir J. 2005;26(2):319–38.CrossRefPubMed
21.
go back to reference Ramirez RD, Sheridan S, Girard L, Sato M, Kim Y, Pollack J, Peyton M, Zou Y, Kurie JM, Dimaio JM, et al. Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res. 2004;64(24):9027–34.CrossRefPubMed Ramirez RD, Sheridan S, Girard L, Sato M, Kim Y, Pollack J, Peyton M, Zou Y, Kurie JM, Dimaio JM, et al. Immortalization of human bronchial epithelial cells in the absence of viral oncoproteins. Cancer Res. 2004;64(24):9027–34.CrossRefPubMed
22.
go back to reference Lam DC, Luo SY, Fu KH, Lui MM, Chan KH, Wistuba GB II, Tsao SW, Ip MS, Minna JD. Nicotinic acetylcholine receptor expression in human airway correlates with lung function. Am J Physiol Lung Cell Mol Physiol. 2016;310(3):L232–9.CrossRefPubMed Lam DC, Luo SY, Fu KH, Lui MM, Chan KH, Wistuba GB II, Tsao SW, Ip MS, Minna JD. Nicotinic acetylcholine receptor expression in human airway correlates with lung function. Am J Physiol Lung Cell Mol Physiol. 2016;310(3):L232–9.CrossRefPubMed
23.
go back to reference Lau WK, Chan SC, Law AC, Ip MS, Mak JC. The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced IL-8 production in human bronchial epithelial cells. Toxicol Sci. 2012;125(2):569–77.CrossRefPubMed Lau WK, Chan SC, Law AC, Ip MS, Mak JC. The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced IL-8 production in human bronchial epithelial cells. Toxicol Sci. 2012;125(2):569–77.CrossRefPubMed
24.
go back to reference Dye BR, Hill DR, Ferguson MA, Tsai YH, Nagy MS, Dyal R, Wells JM, Mayhew CN, Nattiv R, Klein OD, et al. In vitro generation of human pluripotent stem cell derived lung organoids. elife. 2015;4. Dye BR, Hill DR, Ferguson MA, Tsai YH, Nagy MS, Dyal R, Wells JM, Mayhew CN, Nattiv R, Klein OD, et al. In vitro generation of human pluripotent stem cell derived lung organoids. elife. 2015;4.
25.
go back to reference Glushakova O, Kosugi T, Roncal C, Mu W, Heinig M, Cirillo P, Sanchez-Lozada LG, Johnson RJ, Nakagawa T. Fructose induces the inflammatory molecule ICAM-1 in endothelial cells. J Am Soc Nephrol. 2008;19(9):1712–20.CrossRefPubMedPubMedCentral Glushakova O, Kosugi T, Roncal C, Mu W, Heinig M, Cirillo P, Sanchez-Lozada LG, Johnson RJ, Nakagawa T. Fructose induces the inflammatory molecule ICAM-1 in endothelial cells. J Am Soc Nephrol. 2008;19(9):1712–20.CrossRefPubMedPubMedCentral
26.
go back to reference Yao XL, Ikezono T, Cowan M, Logun C, Angus CW, Shelhamer JH. Interferon-gamma stimulates human Clara cell secretory protein production by human airway epithelial cells. Am J Phys. 1998;274(5 Pt 1):L864–9. Yao XL, Ikezono T, Cowan M, Logun C, Angus CW, Shelhamer JH. Interferon-gamma stimulates human Clara cell secretory protein production by human airway epithelial cells. Am J Phys. 1998;274(5 Pt 1):L864–9.
27.
go back to reference Cowan MJ, Huang X, Yao XL, Shelhamer JH. Tumor necrosis factor alpha stimulation of human Clara cell secretory protein production by human airway epithelial cells. Ann N Y Acad Sci. 2000;923:193–201.CrossRefPubMed Cowan MJ, Huang X, Yao XL, Shelhamer JH. Tumor necrosis factor alpha stimulation of human Clara cell secretory protein production by human airway epithelial cells. Ann N Y Acad Sci. 2000;923:193–201.CrossRefPubMed
28.
go back to reference Yoon JM, Lee KH, Lee SM, Lim JJ, Yang SC, Yoo CG, Lee CT, Han SK, Shim YS, Kim YW. The immune modulation of Clara cell-10 in human peripheral monocytes and dendritic cells. Int J Mol Med. 2010;26(3):415–23.PubMed Yoon JM, Lee KH, Lee SM, Lim JJ, Yang SC, Yoo CG, Lee CT, Han SK, Shim YS, Kim YW. The immune modulation of Clara cell-10 in human peripheral monocytes and dendritic cells. Int J Mol Med. 2010;26(3):415–23.PubMed
Metadata
Title
CC16 levels correlate with cigarette smoke exposure in bronchial epithelial cells and with lung function decline in smokers
Authors
David Chi-Leung Lam
Hoi-Hin Kwok
Wai-Cho Yu
Fanny Wai-San Ko
Cheuk-Yin Tam
Arthur Chun-Wing Lau
Daniel Yee-Tak Fong
Mary Sau-Man Ip
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Pulmonary Medicine / Issue 1/2018
Electronic ISSN: 1471-2466
DOI
https://doi.org/10.1186/s12890-018-0607-7

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