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Published in: BMC Pulmonary Medicine 1/2014

Open Access 01-12-2014 | Research article

Airway, but not serum or urinary, levels of YKL-40 reflect inflammation in early cystic fibrosis lung disease

Authors: Emmanuelle Fantino, Catherine L Gangell, Dominik Hartl, Peter D Sly

Published in: BMC Pulmonary Medicine | Issue 1/2014

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Abstract

Background

Cystic fibrosis (CF) lung disease begins in early life and is progressive with the major risk factor being an exaggerated inflammatory response. Currently, assessment of neutrophilic inflammation in early cystic fibrosis (CF) lung disease relies on bronchoalveolar lavage (BAL). The chitinase-like protein YKL-40 is raised in sputum and serum of adults with CF. We investigated YKL-40 in BAL, serum and urine to determine whether this reflected inflammation and infection in young children with CF.

Methods

YKL-40 was measured in matched samples of BAL, serum and urine obtained from 36 infants and young children with CF participating in an early surveillance program. Levels were compared to clinical data and markers of inflammation detected in the lung.

Results

YKL-40 in BAL correlated with pulmonary infection [β=1.30 (SE 0.34), p < 0.001] and BAL markers of inflammation [macrophage number: r2 = 0.34, p < 0.001; neutrophil number: r2 = 0.74, p < 0.001; neutrophil elastase: r2 = 0.47, p < 0.001; CXCL8: r2 = 0.45, p < 0.001; IL-β: r2 = 0.62, p < 0.001]. YKL-40 was detectable in serum but levels did not correlate with BAL levels in the same individuals (r2 = 0.04, p = 0.14) or with inflammatory markers. YKL-40 was below the limit of detection in urine (30 pg/ml).

Conclusions

This study demonstrates that levels of the chitinase-like protein YKL-40 reflect airway inflammation and infection in early CF lung disease. The lack of increased YKL-40 in serum in the absence of systemic inflammation limits the benefit of this potential biomarker in early disease.
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Literature
1.
go back to reference Pillarisetti N, Williamson E, Linnane B, Skoric B, Robertson CF, Robinson P, Massie J, Hall GL, Sly P, Stick S, Ranganathan S: Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am J Respir Crit Care Med. 2011, 184: 75-81. 10.1164/rccm.201011-1892OC.CrossRefPubMed Pillarisetti N, Williamson E, Linnane B, Skoric B, Robertson CF, Robinson P, Massie J, Hall GL, Sly P, Stick S, Ranganathan S: Infection, inflammation, and lung function decline in infants with cystic fibrosis. Am J Respir Crit Care Med. 2011, 184: 75-81. 10.1164/rccm.201011-1892OC.CrossRefPubMed
2.
go back to reference Sly PD, Brennan S, Gangell C, de Klerk N, Murray C, Mott L, Stick SM, Robinson PJ, Robertson CF, Ranganathan SC: Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Respir Crit Care Med. 2009, 180: 146-152. 10.1164/rccm.200901-0069OC.CrossRefPubMed Sly PD, Brennan S, Gangell C, de Klerk N, Murray C, Mott L, Stick SM, Robinson PJ, Robertson CF, Ranganathan SC: Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Respir Crit Care Med. 2009, 180: 146-152. 10.1164/rccm.200901-0069OC.CrossRefPubMed
3.
go back to reference Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan SC, Mott LS, Murray CP, Stick SM: Risk factors for the onset of bronchiectasis in children with cystic fibrosis. N Engl J Med. 1963–1970, 2013: 368- Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan SC, Mott LS, Murray CP, Stick SM: Risk factors for the onset of bronchiectasis in children with cystic fibrosis. N Engl J Med. 1963–1970, 2013: 368-
4.
go back to reference Linnane BM, Hall GL, Nolan G, Brennan S, Stick SM, Sly PD, Robertson CF, Robinson PJ, Franklin PJ, Turner SW, Ranganathan SC: Lung function in infants with cystic fibrosis diagnosed by newborn screening. Am J Respir Crit Care Med. 2008, 178: 1238-1244. 10.1164/rccm.200804-551OC.CrossRefPubMed Linnane BM, Hall GL, Nolan G, Brennan S, Stick SM, Sly PD, Robertson CF, Robinson PJ, Franklin PJ, Turner SW, Ranganathan SC: Lung function in infants with cystic fibrosis diagnosed by newborn screening. Am J Respir Crit Care Med. 2008, 178: 1238-1244. 10.1164/rccm.200804-551OC.CrossRefPubMed
5.
go back to reference Armstrong DS, Hook SM, Jamsen KM, Nixon GM, Carzino R, Carlin JB, Robertson CF, Grimwood K: Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr Pulmonol. 2005, 40: 500-510. 10.1002/ppul.20294.CrossRefPubMed Armstrong DS, Hook SM, Jamsen KM, Nixon GM, Carzino R, Carlin JB, Robertson CF, Grimwood K: Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr Pulmonol. 2005, 40: 500-510. 10.1002/ppul.20294.CrossRefPubMed
6.
go back to reference Douglas TA, Brennan S, Gard S, Berry L, Gangell C, Stick SM, Clements BS, Sly PD: Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis. Eur Respir J. 2009, 33: 305-311.CrossRefPubMed Douglas TA, Brennan S, Gard S, Berry L, Gangell C, Stick SM, Clements BS, Sly PD: Acquisition and eradication of P. aeruginosa in young children with cystic fibrosis. Eur Respir J. 2009, 33: 305-311.CrossRefPubMed
7.
go back to reference Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, Gangell CL, De Klerk N, Linnane B, Ranganathan S, Robinson P, Robertson C, Sly PD: Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr. 2009, 155: 623-628. 10.1016/j.jpeds.2009.05.005. e621CrossRefPubMed Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, Gangell CL, De Klerk N, Linnane B, Ranganathan S, Robinson P, Robertson C, Sly PD: Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr. 2009, 155: 623-628. 10.1016/j.jpeds.2009.05.005. e621CrossRefPubMed
8.
go back to reference Mott LS, Park J, Murray CP, Gangell CL, de Klerk NH, Robinson PJ, Robertson CF, Ranganathan SC, Sly PD, Stick SM: Progression of early structural lung disease in young children with cystic fibrosis. Thorax. 2012, 67: 509-516. 10.1136/thoraxjnl-2011-200912.CrossRefPubMed Mott LS, Park J, Murray CP, Gangell CL, de Klerk NH, Robinson PJ, Robertson CF, Ranganathan SC, Sly PD, Stick SM: Progression of early structural lung disease in young children with cystic fibrosis. Thorax. 2012, 67: 509-516. 10.1136/thoraxjnl-2011-200912.CrossRefPubMed
9.
go back to reference Stick S, Tiddens HA, Aurora P, Davis S, Gustafsson P, Ranganathan S, Robinson P, Rosenfeld M, Sly PD, Ratjen F: Early intervention studies in infants and preschool children with cystic fibrosis; are we ready?. Eur Respir J. 2013, 42: 527-538. 10.1183/09031936.00108212.CrossRefPubMed Stick S, Tiddens HA, Aurora P, Davis S, Gustafsson P, Ranganathan S, Robinson P, Rosenfeld M, Sly PD, Ratjen F: Early intervention studies in infants and preschool children with cystic fibrosis; are we ready?. Eur Respir J. 2013, 42: 527-538. 10.1183/09031936.00108212.CrossRefPubMed
10.
go back to reference Hector A, Kormann MS, Mack I, Latzin P, Casaulta C, Kieninger E, Zhou Z, Yildirim AO, Bohla A, Rieber N, Kappler M, Koller B, Eber E, Eickmeier O, Zielen S, Eickelberg O, Griese M, Mall MA, Hartl D: The chitinase-like protein YKL-40 modulates cystic fibrosis lung disease. PLoS One. 2011, 6: e24399-10.1371/journal.pone.0024399.CrossRefPubMedPubMedCentral Hector A, Kormann MS, Mack I, Latzin P, Casaulta C, Kieninger E, Zhou Z, Yildirim AO, Bohla A, Rieber N, Kappler M, Koller B, Eber E, Eickmeier O, Zielen S, Eickelberg O, Griese M, Mall MA, Hartl D: The chitinase-like protein YKL-40 modulates cystic fibrosis lung disease. PLoS One. 2011, 6: e24399-10.1371/journal.pone.0024399.CrossRefPubMedPubMedCentral
11.
go back to reference Segal SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET: Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2012, 186: 857-865. 10.1164/rccm.201203-0507OC.CrossRef Segal SD, Wagner BD, Anthony MM, Emmett P, Zemanick ET: Sputum biomarkers of inflammation and lung function decline in children with cystic fibrosis. Am J Respir Crit Care Med. 2012, 186: 857-865. 10.1164/rccm.201203-0507OC.CrossRef
12.
go back to reference Laguna TA, Wagner BD, Luckey HK, Mann SA, Segal SD, Regelmann W, Accurso FJ: Sputum desmosine during hospital admission for pulmonary exacerbatin in cystic fibrosis. Chest. 2009, 136: 1561-1568. 10.1378/chest.09-0217.CrossRefPubMedPubMedCentral Laguna TA, Wagner BD, Luckey HK, Mann SA, Segal SD, Regelmann W, Accurso FJ: Sputum desmosine during hospital admission for pulmonary exacerbatin in cystic fibrosis. Chest. 2009, 136: 1561-1568. 10.1378/chest.09-0217.CrossRefPubMedPubMedCentral
13.
go back to reference Volck B, Price PA, Johansen JS, Sorensen O, Benfield TL, Nielsen HJ, Calafat J, Borregaard N: YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils. Proc Assoc Am Physicians. 1998, 110: 351-360.PubMed Volck B, Price PA, Johansen JS, Sorensen O, Benfield TL, Nielsen HJ, Calafat J, Borregaard N: YKL-40, a mammalian member of the chitinase family, is a matrix protein of specific granules in human neutrophils. Proc Assoc Am Physicians. 1998, 110: 351-360.PubMed
14.
go back to reference Kirkpatrick RB, Emery JG, Connor JR, Dodds R, Lysko PG, Rosenberg M: Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages. Exp Cell Res. 1997, 237: 46-54. 10.1006/excr.1997.3764.CrossRefPubMed Kirkpatrick RB, Emery JG, Connor JR, Dodds R, Lysko PG, Rosenberg M: Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages. Exp Cell Res. 1997, 237: 46-54. 10.1006/excr.1997.3764.CrossRefPubMed
15.
go back to reference Kzhyshkowska J, Mamidi S, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S: Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood. 2006, 107: 3221-3228. 10.1182/blood-2005-07-2843.CrossRefPubMed Kzhyshkowska J, Mamidi S, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S: Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood. 2006, 107: 3221-3228. 10.1182/blood-2005-07-2843.CrossRefPubMed
16.
go back to reference Nielsen AR, Plomgaard P, Krabbe KS, Johansen JS, Pedersen BK: IL-6, but not TNF-a, increases plasma YKL-40 in human subjects. Cytokine. 2001, 55: 152-155.CrossRef Nielsen AR, Plomgaard P, Krabbe KS, Johansen JS, Pedersen BK: IL-6, but not TNF-a, increases plasma YKL-40 in human subjects. Cytokine. 2001, 55: 152-155.CrossRef
17.
go back to reference Coffman FD: Chitinase 3-Like-1 (CHI3L1): a putative disease marker at the interface of proteomics and glycomics. Crit Rev Clin Lab Sci. 2008, 45: 531-562. 10.1080/10408360802334743.CrossRefPubMed Coffman FD: Chitinase 3-Like-1 (CHI3L1): a putative disease marker at the interface of proteomics and glycomics. Crit Rev Clin Lab Sci. 2008, 45: 531-562. 10.1080/10408360802334743.CrossRefPubMed
18.
go back to reference Johansen JS, Schultz NA, Jensen BV: Plasma YKL-40: a potential new cancer biomarker?. Future Oncol (London, England). 2009, 5: 1065-1082. 10.2217/fon.09.66.CrossRef Johansen JS, Schultz NA, Jensen BV: Plasma YKL-40: a potential new cancer biomarker?. Future Oncol (London, England). 2009, 5: 1065-1082. 10.2217/fon.09.66.CrossRef
19.
go back to reference Huang K, Wu LD: YKL-40: a potential biomarker for osteoarthritis. J Int Med Res. 2009, 37: 18-24. 10.1177/147323000903700102.CrossRefPubMed Huang K, Wu LD: YKL-40: a potential biomarker for osteoarthritis. J Int Med Res. 2009, 37: 18-24. 10.1177/147323000903700102.CrossRefPubMed
20.
go back to reference Mathiasen AB, Henningsen KM, Harutyunyan MJ, Mygind ND, Kastrup J: YKL-40: a new biomarker in cardiovascular disease?. Biomark Med. 2010, 4: 591-600. 10.2217/bmm.10.58.CrossRefPubMed Mathiasen AB, Henningsen KM, Harutyunyan MJ, Mygind ND, Kastrup J: YKL-40: a new biomarker in cardiovascular disease?. Biomark Med. 2010, 4: 591-600. 10.2217/bmm.10.58.CrossRefPubMed
21.
go back to reference Mygind ND, Iversen K, Kober L, Goetze JP, Nielsen H, Boesgaard S, Bay M, Johansen JS, Nielsen OW, Kirk V, Kastrup J: The inflammatory biomarker YKL-40 at admission is a strong predictor of overall mortality. J Mass Spectrom. 2012 Mygind ND, Iversen K, Kober L, Goetze JP, Nielsen H, Boesgaard S, Bay M, Johansen JS, Nielsen OW, Kirk V, Kastrup J: The inflammatory biomarker YKL-40 at admission is a strong predictor of overall mortality. J Mass Spectrom. 2012
22.
go back to reference Olsson B, Hertze J, Lautner R, Zetterberg H, Nagga K, Hoglund K, Basun H, Annas P, Lannfelt L, Andreasen N, Minthon L, Blennow K, Hansson O: Microglial markers are elevated in the prodromal phase of alzheimer's disease and vascular dementia. J Alzheimers Dis: JAD. 2013, 33: 45-53.PubMed Olsson B, Hertze J, Lautner R, Zetterberg H, Nagga K, Hoglund K, Basun H, Annas P, Lannfelt L, Andreasen N, Minthon L, Blennow K, Hansson O: Microglial markers are elevated in the prodromal phase of alzheimer's disease and vascular dementia. J Alzheimers Dis: JAD. 2013, 33: 45-53.PubMed
23.
go back to reference Hartl D, Lee CG, Da Silva CA, Chupp GL, Elias JA: Novel biomarkers in asthma: chemokines and chitinase-like proteins. Curr Opin Allergy Clin Immunol. 2009, 9: 60-66. 10.1097/ACI.0b013e32831f8ee0.CrossRefPubMed Hartl D, Lee CG, Da Silva CA, Chupp GL, Elias JA: Novel biomarkers in asthma: chemokines and chitinase-like proteins. Curr Opin Allergy Clin Immunol. 2009, 9: 60-66. 10.1097/ACI.0b013e32831f8ee0.CrossRefPubMed
24.
go back to reference Ober C, Chupp GL: The chitinase and chitinase-like proteins: a review of genetic and functional studies in asthma and immune-mediated diseases. Curr Opin Allergy Clin Immunol. 2009, 9: 401-408. 10.1097/ACI.0b013e3283306533.CrossRefPubMedPubMedCentral Ober C, Chupp GL: The chitinase and chitinase-like proteins: a review of genetic and functional studies in asthma and immune-mediated diseases. Curr Opin Allergy Clin Immunol. 2009, 9: 401-408. 10.1097/ACI.0b013e3283306533.CrossRefPubMedPubMedCentral
25.
go back to reference Douglas TA, Brennan S, Berry L, Winfield K, Wainwright CE, Grimwood K, Stick SM, Sly PD: Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis. Thorax. 2010, 65: 985-990. 10.1136/thx.2009.132845.CrossRefPubMed Douglas TA, Brennan S, Berry L, Winfield K, Wainwright CE, Grimwood K, Stick SM, Sly PD: Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis. Thorax. 2010, 65: 985-990. 10.1136/thx.2009.132845.CrossRefPubMed
26.
go back to reference Stutz MD, Gangell CL, Berry LJ, Garratt LW, Sheil B, Sly PD: Cyanide in bronchoalveolar lavage is not diagnostic for Pseudomonas aeruginosa in children with cystic fibrosis. Eur Respir J. 2011, 37: 553-558. 10.1183/09031936.00024210.CrossRefPubMed Stutz MD, Gangell CL, Berry LJ, Garratt LW, Sheil B, Sly PD: Cyanide in bronchoalveolar lavage is not diagnostic for Pseudomonas aeruginosa in children with cystic fibrosis. Eur Respir J. 2011, 37: 553-558. 10.1183/09031936.00024210.CrossRefPubMed
27.
go back to reference Enderby B, Smith D, Carroll W, Lenney W: Hydrogen cyanide as a biomarker for Pseudomonas aeruginosa in the breath of children with cystic fibrosis. Pediatr Pulmonol. 2009, 44: 142-147. 10.1002/ppul.20963.CrossRefPubMed Enderby B, Smith D, Carroll W, Lenney W: Hydrogen cyanide as a biomarker for Pseudomonas aeruginosa in the breath of children with cystic fibrosis. Pediatr Pulmonol. 2009, 44: 142-147. 10.1002/ppul.20963.CrossRefPubMed
28.
go back to reference Ryall B, Davies JC, Wilson R, Shoemark A, Williams HD: Pseudomonas aeruginosa, cyanide accumulatin and lung functin in CF and non-CF bronchiectasis patients. Eur Respir J. 2008, 32: 740-747. 10.1183/09031936.00159607.CrossRefPubMed Ryall B, Davies JC, Wilson R, Shoemark A, Williams HD: Pseudomonas aeruginosa, cyanide accumulatin and lung functin in CF and non-CF bronchiectasis patients. Eur Respir J. 2008, 32: 740-747. 10.1183/09031936.00159607.CrossRefPubMed
29.
go back to reference Ranganathan SC, Parsons F, Gangell C, Brennan S, Stick SM, Sly PD, Fibrosis obotARESTfC: Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis. Thorax. 2011, 66: 408-413. 10.1136/thx.2010.139493.CrossRefPubMed Ranganathan SC, Parsons F, Gangell C, Brennan S, Stick SM, Sly PD, Fibrosis obotARESTfC: Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis. Thorax. 2011, 66: 408-413. 10.1136/thx.2010.139493.CrossRefPubMed
30.
go back to reference Gangell C, Gard S, Douglas T, Park J, de Klerk N, Keil T, Brennan S, Ranganathan S, Robins-Browne R, Sly PD: Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clin Infect Dis. 2011, 53: 425-432. 10.1093/cid/cir399.CrossRefPubMed Gangell C, Gard S, Douglas T, Park J, de Klerk N, Keil T, Brennan S, Ranganathan S, Robins-Browne R, Sly PD: Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clin Infect Dis. 2011, 53: 425-432. 10.1093/cid/cir399.CrossRefPubMed
31.
go back to reference Kornblit B, Helleman D, Munthe-Fog L, Bonde J, Strom JJ, Madsen HO, Johansen JS, Garred P: Plasma YKL-40 and CHI3L1 in systemic inflammation and sepsis – Experience from two prospective cohorts. Immunobiology. 2013, 218: 1227-1234. 10.1016/j.imbio.2013.04.010.CrossRefPubMed Kornblit B, Helleman D, Munthe-Fog L, Bonde J, Strom JJ, Madsen HO, Johansen JS, Garred P: Plasma YKL-40 and CHI3L1 in systemic inflammation and sepsis – Experience from two prospective cohorts. Immunobiology. 2013, 218: 1227-1234. 10.1016/j.imbio.2013.04.010.CrossRefPubMed
32.
go back to reference Kronborg G, Hansen MB, Svenson M, Fomsgaard A, Hoiby N, Bendtzen K: Cytokines in sputum and serum from patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection as markers of destructive inflammation in the lungs. Pediatr Pulmonol. 1993, 15: 292-297. 10.1002/ppul.1950150506.CrossRefPubMed Kronborg G, Hansen MB, Svenson M, Fomsgaard A, Hoiby N, Bendtzen K: Cytokines in sputum and serum from patients with cystic fibrosis and chronic Pseudomonas aeruginosa infection as markers of destructive inflammation in the lungs. Pediatr Pulmonol. 1993, 15: 292-297. 10.1002/ppul.1950150506.CrossRefPubMed
33.
go back to reference Wolter JM, Rodwell RL, Bowler SD, McCormack JG: Cytokines and inflammatory mediators do not indicate acute infection in cystic fibrosis. Clin Diagn Lab Immunol. 1999, 6: 260-265.PubMedPubMedCentral Wolter JM, Rodwell RL, Bowler SD, McCormack JG: Cytokines and inflammatory mediators do not indicate acute infection in cystic fibrosis. Clin Diagn Lab Immunol. 1999, 6: 260-265.PubMedPubMedCentral
Metadata
Title
Airway, but not serum or urinary, levels of YKL-40 reflect inflammation in early cystic fibrosis lung disease
Authors
Emmanuelle Fantino
Catherine L Gangell
Dominik Hartl
Peter D Sly
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Pulmonary Medicine / Issue 1/2014
Electronic ISSN: 1471-2466
DOI
https://doi.org/10.1186/1471-2466-14-28

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