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

BMC Pulmonary Medicine

Peter D Sly¹  Dominik Hartl²  Catherine L Gangell¹  Emmanuelle Fantino¹ 

[1] The Queensland Children’s Medical Research Institute, The University of Queensland, Level 4, Foundation Building, Royal Children’s Hospital, Herston road, Herston, Brisbane, QLD 4059, Australia;Department of Pediatrics, Section of Immunology and Infectious Diseases, University of Tubingen, Tubingen 72076, Germany

关键词: Lung disease;    Biomarker;    YKL-40;    Cystic fibrosis;   

Others  :  866552
DOI  :  10.1186/1471-2466-14-28

 received in 2013-10-02, accepted in 2014-02-24,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Fantino et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]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.
• [2]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.
• [3]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]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.
• [5]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.
• [6]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.
• [7]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. e621
• [8]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.
• [9]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]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.
• [11]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.
• [12]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.
• [13]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.
• [14]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.
• [15]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.
• [16]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.
• [17]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.
• [18]Johansen JS, Schultz NA, Jensen BV: Plasma YKL-40: a potential new cancer biomarker? Future Oncol (London, England) 2009, 5:1065-1082.
• [19]Huang K, Wu LD: YKL-40: a potential biomarker for osteoarthritis. J Int Med Res 2009, 37:18-24.
• [20]Mathiasen AB, Henningsen KM, Harutyunyan MJ, Mygind ND, Kastrup J: YKL-40: a new biomarker in cardiovascular disease? Biomark Med 2010, 4:591-600.
• [21]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]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.
• [23]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.
• [24]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.
• [25]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.
• [26]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.
• [27]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.
• [28]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.
• [29]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.
• [30]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.
• [31]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.
• [32]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.
• [33]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.