Top

Published in:

Open Access 01-12-2016 | Research

Elevated levels of FN1 and CCL2 in bronchoalveolar lavage fluid from sarcoidosis patients

Authors: Carl Hamsten, Emil Wiklundh, Hans Grönlund, Jochen M. Schwenk, Mathias Uhlén, Anders Eklund, Peter Nilsson, Johan Grunewald, Anna Häggmark-Månberg

Published in: Respiratory Research | Issue 1/2016

Abstract

Background

Sarcoidosis is a granulomatous systemic inflammatory disease in which more than 90 % of all patients develop pulmonary manifestations. Several gene associations have previously been described, but established and clinically useful biomarkers are still absent. This study aimed to find proteins in bronchoalveolar lavage (BAL) fluid that can be associated with the disease.

Methods

We developed and performed profiling of 94 selected proteins in BAL fluid and serum samples obtained from newly diagnosed and non-treated patients with sarcoidosis. Using multiplexed immunoassays, a total of 317 BAL and 217 serum samples were analyzed, including asthmatic patients and healthy individuals as controls.

Results

Our analyses revealed increased levels of eight proteins in sarcoidosis patients compared to controls. Out of these, fibronectin (FN1) and C-C motif chemokine 2 (CCL2) revealed the strongest associations. In addition, cadherin 5 (CDH5) was found to correlate positively with lymphocyte cell numbers in BAL fluid.

Conclusions

Applying a high throughput proteomics screening technique, we found proteins of potential clinical relevance in the context of sarcoidosis.

Available only for authorised users

Broos CE. Granuloma formation in pulmonary. Sarcoidosis. 2013;4:437.

Grunewald J, Eklund A. Lofgren’s syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med. 2009;179:307–12.CrossRefPubMed

Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med. 2007;357:2153–65.CrossRefPubMed

Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997;336:1224–34.CrossRefPubMed

Cox CE, Donohue JF, Brown CD, Kataria YP, Judson MA. Health-related quality of life of persons with sarcoidosis. Chest. 2004;125:997–1004.CrossRefPubMed

Bons JA, Drent M, Bouwman FG, Mariman EC, van Dieijen-Visser MP, Wodzig WK. Potential biomarkers for diagnosis of sarcoidosis using proteomics in serum. Respir Med. 2007;101:1687–95.CrossRefPubMed

Beirne P, Pantelidis P, Charles P, Wells AU, Abraham DJ, Denton CP, Welsh KI, Shah PL, du Bois RM, Kelleher P. Multiplex immune serum biomarker profiling in sarcoidosis and systemic sclerosis. Eur Respir J. 2009;34:1376–82.CrossRefPubMed

Silva E, Souchelnytskyi S, Kasuga K, Eklund A, Grunewald J, Wheelock AM. Quantitative intact proteomics investigations of alveolar macrophages in sarcoidosis. Eur Respir J. 2013;41:1331–9.CrossRefPubMed

Byström S, Ayoglu B, Häggmark A, Mitsios N, Hong M-G, Drobin K, Forsström B, Fredolini C, Khademi M, Amor S, et al. Affinity proteomic profiling of plasma, cerebrospinal fluid, and brain tissue within multiple sclerosis. J Proteome Res. 2014;13(11):4607–19.

10.

Bachmann J, Burte F, Pramana S, Conte I, Brown BJ, Orimadegun AE, Ajetunmobi WA, Afolabi NK, Akinkunmi F, Omokhodion S, et al. Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria. PLoS Pathog. 2014;10:e1004038.CrossRefPubMedPubMedCentral

11.

Karimi R, Tornling G, Grunewald J, Eklund A, Skold CM. Cell recovery in bronchoalveolar lavage fluid in smokers is dependent on cumulative smoking history. PLoS One. 2012;7:e34232.CrossRefPubMedPubMedCentral

12.

Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, Eklund A, Kitaichi M, Lynch J, Rizzato G, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis. 1999;16:149–73.PubMed

13.

Schwenk JM, Gry M, Rimini R, Uhlen M, Nilsson P. Antibody suspension bead arrays within serum proteomics. J Proteome Res. 2008;7:3168–79.CrossRefPubMed

14.

Häggmark A, Byström S, Ayoglu B, Qundos U, Uhlén M, Khademi M, et al. Antibody-based profiling of cerebrospinal fluid within multiple sclerosis. Proteomics. 2013;13:2256–67.

15.

Dezfouli M, Vickovic S, Iglesias MJ, Nilsson P, Schwenk JM, Ahmadian A. Magnetic bead assisted labeling of antibodies at nanogram scale. Proteomics. 2014;14:14–8.CrossRefPubMed

16.

Ihaka R, Gentleman R. R: a language for data analysis and graphics. J Comput Graph Stat. 1996;5(3):299–314.

17.

Dieterle F, Ross A, Schlotterbeck G, Senn H. Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in 1H NMR metabonomics. Anal Chem. 2006;78:4281–90.CrossRefPubMed

18.

Kato BS, Nicholson G, Neiman M, Rantalainen M, Holmes CC, Barrett A, Uhlen M, Nilsson P, Spector TD, Schwenk JM. Variance decomposition of protein profiles from antibody arrays using a longitudinal twin model. Proteome Sci. 2011;9:73.CrossRefPubMedPubMedCentral

19.

Mosher DF. Physiology of fibronectin. Annu Rev Med. 1984;35:561–75.CrossRefPubMed

20.

Blaschke E, Eklund A, Hernbrand R. Determination of fibronectin and its degradation products in bronchoalveolar lavage fluid. Scand J Clin Lab Invest. 1990;50:619–25.CrossRefPubMed

21.

Rennard SI, Crystal RG. Fibronectin in human bronchopulmonary lavage fluid. Elevation in patients with interstitial lung disease. J Clin Invest. 1982;69:113–22.CrossRefPubMedPubMedCentral

22.

O’Connor C, Odlum C, Van Breda A, Power C, Fitzgerald MX. Collagenase and fibronectin in bronchoalveolar lavage fluid in patients with sarcoidosis. Thorax. 1988;43:393–400.CrossRefPubMedPubMedCentral

23.

Blaschke E, Eklund A, Hernbrand R. Extracellular matrix components in bronchoalveolar lavage fluid in sarcoidosis and their relationship to signs of alveolitis. Am Rev Respir Dis. 1990;141:1020–5.CrossRefPubMed

24.

Wolff H, Teppo AM, Mutanen P, Sutinen S, Backman R, Sutinen S, Pietinalho A, Riska H. Studies of cytokine levels in bronchoalveolar fluid lavage from patients with interstitial lung diseases. Scand J Clin Lab Invest. 2003;63:27–36.CrossRefPubMed

25.

Lalancette M, Carrier G, Laviolette M, Ferland S, Rodrique J, Begin R, Cantin A, Cormier Y. Farmer’s lung. Long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis. 1993;148:216–21.CrossRefPubMed

26.

Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29:313–26.CrossRefPubMedPubMedCentral

27.

Palchevskiy V, Hashemi N, Weigt SS, Xue YY, Derhovanessian A, Keane MP, Strieter RM, Fishbein MC, Deng JC, Lynch JP, 3rd, et al. Immune response CC chemokines CCL2 and CCL5 are associated with pulmonary sarcoidosis. Fibrogenesis Tissue Repair. 2011;4:10.CrossRefPubMedPubMedCentral

28.

Car BD, Meloni F, Luisetti M, Semenzato G, Gialdroni-Grassi G, Walz A. Elevated IL-8 and MCP-1 in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and pulmonary sarcoidosis. Am J Respir Crit Care Med. 1994;149:655–9.CrossRefPubMed

29.

Iida K, Kadota J, Kawakami K, Matsubara Y, Shirai R, Kohno S. Analysis of T cell subsets and beta chemokines in patients with pulmonary sarcoidosis. Thorax. 1997;52:431–7.CrossRefPubMedPubMedCentral

30.

Christophi GP, Caza T, Curtiss C, Gumber D, Massa PT, Landas SK. Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis. Exp Mol Pathol. 2014;96:393–9.CrossRefPubMedPubMedCentral

31.

Rivera NV, Ronninger M, Shchetynsky K, Franke A, Nothen MM, Muller-Quernheim J, Schreiber S, Adrianto I, Karakaya B, van Moorsel CH, et al. High-density genetic mapping identifies new susceptibility variants in sarcoidosis phenotypes and shows genomic-driven phenotypic differences. Am J Respir Crit Care Med. 2016;193(9):1008–22.

32.

Magi B, Bargagli E, Bini L, Rottoli P. Proteome analysis of bronchoalveolar lavage in lung diseases. Proteomics. 2006;6:6354–69.CrossRefPubMed

33.

Jones KP, Edwards JH, Reynolds SP, Peters TJ, Davies BH. A comparison of albumin and urea as reference markers in bronchoalveolar lavage fluid from patients with interstitial lung disease. Eur Respir J. 1990;3:152–6.PubMed

34.

Ward C, Fenwick J, Booth H, Walters EH. Albumin is not suitable as a marker of bronchoalveolar lavage dilution in interstitial lung disease. Eur Respir J. 1997;10:2029–33.CrossRefPubMed

35.

Häggmark A, Hamsten C, Wiklundh E, Lindskog C, Mattsson C, Andersson E, Lundberg IE, Gronlund H, Schwenk JM, Eklund A, et al. Proteomic profiling reveals autoimmune targets in sarcoidosis. Am J Respir Crit Care Med. 2015;191:574–83.CrossRefPubMed

36.

Landi C, Bargagli E, Bianchi L, Gagliardi A, Carleo A, Bennett D, et al. Towards a functional proteomics approach to the comprehension of idiopathic pulmonary fibrosis, sarcoidosis, systemic sclerosis and pulmonary Langerhans cell histiocytosis. J Proteomics. 2013;83:60–75.

37.

Zhang Y, Chen X, Hu Y, Du S, Shen L, He Y, et al. Preliminary characterizations of a serum biomarker for sarcoidosis by comparative proteomic approach with tandem-mass spectrometry in ethnic Han Chinese patients. Respir Res. 2013;14:18.

38.

Sabounchi-Schutt F, Astrom J, Hellman U, Eklund A, Grunewald J. Changes in bronchoalveolar lavage fluid proteins in sarcoidosis: a proteomics approach. Eur Respir J. 2003;21:414–20.

39.

Rottoli P, Magi B, Perari MG, Liberatori S, Nikiforakis N, Bargagli E, Cianti R, Bini L, Pallini V. Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis. Proteomics. 2005;5:1423–30.

Title: Elevated levels of FN1 and CCL2 in bronchoalveolar lavage fluid from sarcoidosis patients
Authors: Carl Hamsten
Emil Wiklundh
Hans Grönlund
Jochen M. Schwenk
Mathias Uhlén
Anders Eklund
Peter Nilsson
Johan Grunewald
Anna Häggmark-Månberg
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Respiratory Research / Issue 1/2016
Electronic ISSN: 1465-993X
DOI: https://doi.org/10.1186/s12931-016-0381-0

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Elevated levels of FN1 and CCL2 in bronchoalveolar lavage fluid from sarcoidosis patients

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

Induction of pulmonary antibodies against oxidized lipids in mice exposed to cigarette smoke

Regulation of transforming growth factor-beta1 (TGF-β1)-induced pro-fibrotic activities by circadian clock gene BMAL1

Increased expression of TROP2 in airway basal cells potentially contributes to airway remodeling in chronic obstructive pulmonary disease

Risk factors for mortality in patients admitted to intensive care units with pneumonia

Airway epithelial cell exposure to distinct e-cigarette liquid flavorings reveals toxicity thresholds and activation of CFTR by the chocolate flavoring 2,5-dimethypyrazine

Erratum to: Risk factors for mortality in patients admitted to intensive care units with pneumonia

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page