[en] Systemic sclerosis (SSc) is a potentially serious and disabling connective tissue disease specially in case of interstitial lung disease (SSc-ILD). The aim of our study was to evaluate the potential utility of dosing in the induced sputum (IS) and to compare their levels in SSc-ILD and SSc-nonILD patients, as well as in healthy volunteers (HV). IS and sera values were also compared. In a prospective cross-sectional analysis, we studied the IS and serum provided from 25 SSc patients, 15 SSc-nonILD and 10 SSc-ILD, compared to 25 HV. We analyzed sputum cell composition and quantified in the supernatant and corresponding serum by commercially available immunoassays: IGFBP-1, IGFBP-2, IGFBP-3, TGF-β, IL-8, TNF-α, YKL-40, MMP-7 and MMP-9. Lung function was studied by the determination of FEV-1 (%), FVC (%), DLCO (%) and KCO (%). The IS of SSc patients had a lower weight than HV (p<0.05, p<0.01) without any significant difference with regard to the cellularity. IGFBP-1 (p < 0.0001), TGF-β (p < 0.05), IL-8 (p < 0.05), YKL-40 (p < 0.0001) and MMP-7 (p < 0.01) levels were increased in the IS of SSc patients compared to HV. Only IL-8 serum levels (p < 0.001) were increased in SSc patients compared to HV. Neither in IS nor in serum were observed differences between SSc-ILD and SSc-nonILD patients. Correlations were observed between IS IL-8 levels and FEV-1 (%) (r = = - 0.53, p < 0.01), FVC (%) (r = - 0.51, p < 0.01) and annualized ∆KCO (%) (r = 0.57, p < 0.05), between IS TGF-β levels and annualized ∆FEV-1 (%) (r = = - 0.57, p < 0.05), between IS IGFBP-2 levels and annualized ∆KCO (%) (r = 0.56, p < 0.05). Our study showed that SSc patients exhibit raised IS levels of IGFBP-1, TGF-β, IL-8, YKL-40 and MMP-7, molecules known to be involved in lung remodeling and fibrotic process, without any significant difference between SSc-ILD and SSc-nonILD patients. IL-8, TGF-β and IGFBP-2 are correlated with lung function in SSc patients which emphasize clinical relevance. IS analysis represents a new approach to understand lung inflammatory process in SSc patients. A longitudinal study is needed to evaluate their pathophysiological relevance.
Disciplines :
Cardiovascular & respiratory systems Rheumatology
Author, co-author :
JACQUERIE, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
HENKET, Monique ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
André, B; Rheumatology Department, CHU Liège, GIGA Research, ULiège, University Hospital of Liege, Domaine Universitaire du Sart-Tilman, B35, 4020, Liège, Belgium
MOERMANS, Catherine ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
DE SENY, Dominique ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
GESTER, Fanny ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
LOUIS, Renaud ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
MALAISE, Michel ; Centre Hospitalier Universitaire de Liège - CHU > > Service de rhumatologie
GUIOT, Julien ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pneumologie - allergologie
Language :
English
Title :
Inflammatory profile of induced sputum composition in systemic sclerosis and comparison with healthy volunteers.
Allanore, Y. Pathophysiology of systemic sclerosis. Med. Sci. (Paris) 32, 183–191 (2016). DOI: 10.1051/medsci/20163202012
Schoenfeld, S. R. & Castelino, F. V. Interstitial lung disease in scleroderma. Rheum. Dis. Clin. N. Am. 41(2), 237–248 (2015). DOI: 10.1016/j.rdc.2014.12.005
Hachulla, E. et al. Is pulmonary arterial hypertension really a late complication of systemic sclerosis?. Chest 136(5), 1211–1219. 10.1378/chest.08-3042 (2009) (Epub 2009 May 8). DOI: 10.1378/chest.08-3042
Teixeira, L. et al. Mortality and risk factors of scleroderma renal crisis: A French retrospective study of 50 patients. Ann. Rheum. Dis. 67(1), 110–116 (2008). DOI: 10.1136/ard.2006.066985
Guiot, J. et al. L’hypertension artérielle pulmonaire. Rev. Med. Liege 74(3), 139–145 (2019).
Guiot, J., Cornia, O. & Louis, R. Pulmonary arterial hypertension (PAH): A new era of pulmonary arterial vasodilatators. Rev. Med. Liege 75(5–6), 344–349 (2020).
Gester, F., Duysinx, B., Von Frenckell, C., Louis, R. & Guiot, J. Pattern of biological changes in interstitial lung diseases. Rev. Med. Liege 74(1), 47–53 (2019).
Herzog, E. L. et al. Review: Interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis: How similar and distinct?. Arthritis Rheumatol. 66, 1967 (2014). DOI: 10.1002/art.38702
Highland, K. B. & Silver, R. M. New developments in scleroderma interstitial lung disease. Curr. Opin. Rheumatol. 17, 737 (2005). DOI: 10.1097/01.bor.0000181534.67685.5a
Al-Dhaher, F. F., Pope, J. E. & Ouimet, J. M. Determinants of morbidity and mortality of systemic sclerosis in Canada. Semin. Arthritis Rheum. 39, 269 (2010). DOI: 10.1016/j.semarthrit.2008.06.002
Mathai, S. C. et al. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: Impact of interstitial lung disease. Arthritis Rheum. 60, 569 (2009). DOI: 10.1002/art.24267
Gilson, M. et al. Prognostic factors for lung function in systemic sclerosis: Prospective study of 105 cases. Eur. Respir. J. 35, 112 (2010). DOI: 10.1183/09031936.00060209
Branley, H. M. Pulmonary fibrosis in systemic sclerosis: Diagnosis and management. Respir. Med. CME. 3, 10–14 (2010). DOI: 10.1016/j.rmedc.2009.09.016
Schurawitzki, H. et al. Interstitial lung disease in progressive systemic sclerosis: High-resolution CT versus radiography. Radiology 176, 755–759 (1990). DOI: 10.1148/radiology.176.3.2389033
McNearney, T. A. et al. Pulmonary involvement in systemic sclerosis: Associations with genetic, serologic, sociodemographic, and behavioral factors. Arthritis Rheum. 57, 318–326 (2007). DOI: 10.1002/art.22532
Fischer, A. et al. Clinically significant interstitial lung disease in limited scleroderma: Histopathology, clinical features, and survival. Chest 134, 601 (2008). DOI: 10.1378/chest.08-0053
King, T. E. Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am. J. Respir. Crit. Care Med. 172, 268 (2005). DOI: 10.1164/rccm.200503-483OE
Pellegrino, R. et al. Interpretative strategies for lung function tests. Eur. Respir. J. 26, 948–968. 10.1183/09031936.05.00035205 (2005). DOI: 10.1183/09031936.05.00035205
Cramer, D. et al. Bronchoalveolar lavage cellular profiles in patients with systemic sclerosis-associated interstitial lung disease are not predictive of disease progression. Arthritis Rheum. 56(6), 2005–2012 (2007). DOI: 10.1002/art.22696
Steen, V. Predictors of end stage lung disease in systemic sclerosis. Ann. Rheum. Dis. 62, 97 (2003). DOI: 10.1136/ard.62.2.97
Fahy, J. V., Wong, H., Liu, J. & Boushey, H. A. Comparison of samples collected by sputum induction and bronchoscopy from asthmatics and healthy subjects. Am. J. Respir. Crit. Care Med. 152(1), 53–58 (1995). DOI: 10.1164/ajrccm.152.1.7599862
Guiot, J., Henket, M., Corhay, J. L., Moermans, C. & Louis, R. Sputum biomarkers in IPF: Evidence for raised gene expression and protein level of IGFBP-2, IL-8 and MMP-7. PLoS One 12(2), e0171344 (2017). DOI: 10.1371/journal.pone.0171344
Guiot, J. et al. Methodology for sputum induction and laboratory processing. J. Vis. Exp. 130, e56612. 10.3791/56612 (2017). DOI: 10.3791/56612
Litinsky, I. Induced Sputum analysis in subjects with systemic sclerosis. Respir. Care 61(10), 1369–1373 (2016). DOI: 10.4187/respcare.04706
Damjanov, N. et al. Induced sputum in systemic sclerosis interstitial lung disease: Comparison to healthy controls and bronchoalveolar lavage. Respiration 78, 56–62 (2009). DOI: 10.1159/000164720
Yilmaz, N. et al. Induced sputum as a method for detection of systemic sclerosis-related interstitial lung disease. Rheumatol. Int. 32(7), 1921–1925 (2012). DOI: 10.1007/s00296-011-1872-4
Balestro, E. et al. Immune inflammation and disease progression in idiopathic pulmonary fibrosis. PLoS One 11(5), e0154516. 10.1371/journal.pone.0154516 (2016). DOI: 10.1371/journal.pone.0154516
Bonhomme, O. et al. Biomarkers in systemic sclerosis-associated interstitial lung disease: Review of the literature. Rheumatology (Oxford) 10.1093/rheumatology/kez230 (2019). DOI: 10.1093/rheumatology/kez230
Yilmaz, N., Olgun, S., Ahiskali, R., Karakurt, S. & Yavuz, S. Decreased sputum caveolin-1 is associated with systemic sclerosis related lung disease. Sarcoidosis Vasc. Diffuse Lung Dis. 31(1), 55–61 (2014).
van den Hoogen, F. 2013 Classification criteria for systemic sclerosis: An American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 65(11), 2737–2747 (2013). DOI: 10.1002/art.38098
LeRoy, E. C. et al. Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J. Rheumatol. 15(2), 202–205 (1988).
LeRoy, E. C. & Medsger, T. A. Jr. Criteria for the classification of early systemic sclerosis. J. Rheumatol. 28(7), 1573–1576 (2001).
Poormoghim, H., Lucas, M., Fertig, N. & Medsger, T. A. Jr. Systemic sclerosis sine scleroderma: Demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum. 43(2), 444–451 (2000). DOI: 10.1002/1529-0131(200002)43:2<444::AID-ANR27>3.0.CO;2-G
A U Wells, D M Hansell, B Corrin, N K Harrison, P Goldstraw, C M Black, R M du Bois. High resolution computed tomography as a predictor of lung histology in systemic sclerosis. Thorax, 47(9): 738-42. https://doi.org/10.1136/thx.47.9.738. (1992)
Inoue, Y. et al. Diagnostic and prognostic biomarkers of chronic fibrosing interstitial lung diseases with a progressive phenotype. Chest S0012–3692(20), 30569–30579. 10.1016/j.chest.2020.03.037 (2020). DOI: 10.1016/j.chest.2020.03.037
Raghu, G. et al. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 183(6), 788–824 (2011). DOI: 10.1164/rccm.2009-040GL
Fernandez, I. E. & Eickelberg, O. The impact of TGF-b on lung fibrosis. Proc. Am. Thorac. Soc. 9, 1116 (2012). DOI: 10.1513/pats.201203-023AW
Fastrès, A. et al. Microbiome in idiopathic pulmonary fibrosis: A promising approach for targeted therapies. Int. J. Mol. Sci. 18, 12. 10.3390/ijms18122735 (2017). DOI: 10.3390/ijms18122735
Poulet, C. et al. Exosomal long non-coding RNA in lung diseases. Int. J. Mol. Sci. 21(10), 3580 (2020). DOI: 10.3390/ijms21103580
Guiot, J. et al. Altered epigenetic features in circulating nucleosomes in idiopathic pulmonary fibrosis. Clin. Epigenet. 9, 84. 10.1186/s13148-017-0383-x (2017). DOI: 10.1186/s13148-017-0383-x
Khanna, D. et al. An open-label, phase II study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease: The LOTUSS trial. J. Rheumatol. 43(9), 1672–1679. 10.3899/jrheum.151322 (2016) (Epub 2016 Jul 1). DOI: 10.3899/jrheum.151322
Huh, J. W. et al. Is metalloproteinase-7 specific for idiopathic pulmonary fibrosis?. Chest 133(5), 1101–1106. 10.1378/chest.07-2116 (2008). DOI: 10.1378/chest.07-2116
Guiot, J., Moermans, C., Henket, M., Corhay, J. L. & Louis, R. Blood biomarkers in idiopathic pulmonary fibrosis. Lung 195(3), 273–280. 10.1007/s00408-017-9993-5 (2017) (Epub 2017 Mar 28). DOI: 10.1007/s00408-017-9993-5
Kennedy, B. et al. Biomarkers to identify ILD and predict lung function decline in scleroderma lung disease or idiopathic pulmonary fibrosis. Sarcoidosis Vasc. Diffuse Lung Dis. 32(3), 228–236 (2015).
Moinzadeh, P. et al. Elevated MMP-7 levels in patients with systemic sclerosis: Correlation with pulmonary involvement. Exp. Dermatol. 20(9), 770–773. 10.1111/j.1600-0625.2011.01321.x (2011) (Epub 2011 Jun 26). DOI: 10.1111/j.1600-0625.2011.01321.x
Distler, O. et al. Nintedanib for systemic sclerosis-associated interstitial lung disease. N. Engl. J. Med. 380(26), 2518–2528. 10.1056/NEJMoa1903076 (2019). DOI: 10.1056/NEJMoa1903076
Wells, A. et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnostis in the INBUILD trial: A randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir. 8(5), 453–460. 10.1016/S2213-2600(20)30036-9 (2020). DOI: 10.1016/S2213-2600(20)30036-9
Duan, C. & Xu, Q. Roles of insulin-like growth factor (IGF) binding proteins in regulating IGF actions. Gen. Comp. Endocrinol. 142(1–2), 44–52 (2005). DOI: 10.1016/j.ygcen.2004.12.022
Yau, S. W., Azar, W. J., Sabin, M. A., Werther, G. A. & Russo, V. C. IGFBP-2—taking the lead in growth, metabolism and cancer. J. Cell Commun. Signal. 9(2), 125–142 (2015). DOI: 10.1007/s12079-015-0261-2
Guiot, J., Bondue, B., Henket, M., Corhay, J. L. & Louis, R. Raised serum levels of IGFBP-1 and IGFBP-2 in idiopathic pulmonary fibrosis. BMC Pulm. Med. 16(1), 86. 10.1186/s12890-016-0249-6 (2016). DOI: 10.1186/s12890-016-0249-6
Shao, R. et al. YKL-40, a secreted glycoprotein, promotes tumor angiogenesis. Oncogene 28(50), 4456–4468 (2009). DOI: 10.1038/onc.2009.292
Catalán, V. et al. Increased circulating and visceral adipose tissue expression levels of YKL-40 in obesity-associated type 2 diabetes are related to inflammation: Impact of conventional weight loss and gastric bypass. J. Clin. Endocrinol. Metab. 96(1), 200–209 (2011). DOI: 10.1210/jc.2010-0994
Furuhashi, K. et al. Increased expression of YKL-40, a chitinase-like protein, in serum and lung of patients with idiopathic pulmonary fibrosis. Respir. Med. 104(8), 1204–1210 (2010). DOI: 10.1016/j.rmed.2010.02.026
Zheng, J. L. et al. Increased serum YKL-40 and C-reactive protein levels are associated with angiographic lesion progression in patients with coronary artery disease. Atherosclerosis 210(2), 590–595 (2010). DOI: 10.1016/j.atherosclerosis.2009.12.016
Tong, X. et al. The YKL-40 protein is a potential biomarker for COPD: A meta-analysis and systematic review. Int. J. Chron. Obstruct.Pulmon. Dis. 2018(13), 409–418. 10.2147/COPD.S152655 (2018) (eCollection). DOI: 10.2147/COPD.S152655
Korthagen, N. M. et al. Serum and BALF YKL-40 levels are predictors of survival in idiopathic pulmonary fibrosis. Respir. Med. 105(1), 106–113. 10.1016/j.rmed.2010.09.012 (2011). DOI: 10.1016/j.rmed.2010.09.012
Yang, X. & Sheng, G. YKL-40 levels are associated with disease severity and prognosis of viral pneumonia, but not available in bacterial pneumonia in children. BMC Pediatr. 18(1), 381. 10.1186/s12887-018-1345-y (2018). DOI: 10.1186/s12887-018-1345-y
Long, X. et al. Serum YKL-40 as predictor of outcome in hypersensitivity pneumonitis. Eur. Respir. J. 23(49), 2. 10.1183/13993003.01924-2015 (2017). DOI: 10.1183/13993003.01924-2015
Schnyder, B., Bogdan, J. A. Jr. & Schnyder-Candrian, S. Role of interleukin-8 phosphorylated kinases in stimulating neutrophil migration through fibrin gels. Lab. Investig. J. Tech. Methods Pathol. 79(11), 1403–1413 (1999).
Ziegenhagen, M. W., Zabel, P., Zissel, G., Schlaak, M. & Muller-Quernheim, J. Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity. Am. J. Respir. Crit. Care Med. 157(3 Pt 1), 762–768 (1998). DOI: 10.1164/ajrccm.157.3.9705014
Beeh, K. M., Beier, J., Kornmann, O. & Buhl, R. Neutrophilic inflammation in induced sputum of patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc. Diffuse Lung Dis. 20(2), 138–143 (2003).
Schmidt, K. et al. Bronchoalveoloar Lavage fluid cytokines and chemokines as markers and predictors for the outcome of interstitial lung disease in systemic sclerosis patients. Arthritis Res. Ther. 11(4), R111. 10.1186/ar2766 (2009) (Epub 2009 Jul 17). DOI: 10.1186/ar2766
