Skip to main content
Top
Published in: BMC Musculoskeletal Disorders 1/2015

Open Access 01-12-2015 | Research article

Cross-sectional study of soluble selectins, fractions of circulating microparticles and their relationship to lung and skin involvement in systemic sclerosis

Authors: Line V. Iversen, Susanne Ullman, Ole Østergaard, Christoffer T. Nielsen, Poul Halberg, Tonny Karlsmark, Niels H.H. Heegaard, Søren Jacobsen

Published in: BMC Musculoskeletal Disorders | Issue 1/2015

Login to get access

Abstract

Background

Endothelial damage and activation may play central roles in the pathogenesis of systemic sclerosis (SSc) and are reflected by microparticles (MPs) and soluble selectins. The objective of this study was to determine if these potential biomarkers are associated with specific organ involvements or cutaneous subgroups of SSc patients.

Method

MPs in platelet-poor plasma from 121 patients with SSc, 79 and 42 with limited and diffuse cutaneous disease, respectively, were characterized by flow cytometry for their capacity to bind annexin V in combination with surface markers of either platelets (PMPs), leukocytes (LMPs) or endothelial cells (EMPs). Soluble E- and P-selectin levels were determined in plasma. By correlation analyses, this was held against involvement of skin, lung function, lung fibrosis, pulmonary artery hypertension, and serology.

Results

None of the markers were associated with cutaneous subgroups of SSc. Concentrations of annexin V non-binding EMPs and annexin V non-binding LMPs were negatively correlated to pulmonary diffusing capacity (DLCO) (r = -0.28; p = 0.003; r = -0.26; p = 0.005) and forced vital capacity (FVC) (r = -0.24; p = 0.009; r = -0.29; p = 0.002), driven by patients with limited and diffuse cutaneous disease, respectively. Soluble E-selectin levels correlated negatively to DLCO (r = -0.21, p = 0.03) and FVC (r = -0.25; p = 0.007); and soluble P-selectin correlated negatively to DLCO (r = -0.23, p = 0.01).

Conclusion

Negative correlations between annexin V non-binding EMP and LMP concentrations with lung function parameters (DLCO and FVC) differed between limited and diffuse cutaneous subsets of SSc, indicative of various pathogeneses of lung involvement in SSc, possibly with a differential role of MPs.
Literature
2.
go back to reference Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24:165–70.CrossRefPubMed Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24:165–70.CrossRefPubMed
3.
go back to reference Cox SR, Walker JG, Coleman M, Rischmueller M, Proudman S, Smith MD, et al. Isolated pulmonary hypertension in scleroderma. Intern Med J. 2005;35:28–33.CrossRefPubMed Cox SR, Walker JG, Coleman M, Rischmueller M, Proudman S, Smith MD, et al. Isolated pulmonary hypertension in scleroderma. Intern Med J. 2005;35:28–33.CrossRefPubMed
4.
go back to reference Steen V, Medsger Jr TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48:516–22.CrossRefPubMed Steen V, Medsger Jr TA. Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum. 2003;48:516–22.CrossRefPubMed
5.
go back to reference Morelli S, Barbieri C, Sgreccia A, Ferrante L, Pittoni V, Conti F, et al. Relationship between cutaneous and pulmonary involvement in systemic sclerosis. J Rheumatol. 1997;24:81–5.PubMed Morelli S, Barbieri C, Sgreccia A, Ferrante L, Pittoni V, Conti F, et al. Relationship between cutaneous and pulmonary involvement in systemic sclerosis. J Rheumatol. 1997;24:81–5.PubMed
6.
go back to reference Hanitsch LG, Burmester GR, Witt C, Hunzelmann N, Genth E, Krieg T, et al. Skin sclerosis is only of limited value to identify SSc patients with severe manifestations-an analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register. Rheumatology (Oxford). 2009;48:70–3.CrossRef Hanitsch LG, Burmester GR, Witt C, Hunzelmann N, Genth E, Krieg T, et al. Skin sclerosis is only of limited value to identify SSc patients with severe manifestations-an analysis of a distinct patient subgroup of the German Systemic Sclerosis Network (DNSS) Register. Rheumatology (Oxford). 2009;48:70–3.CrossRef
7.
go back to reference Jacobsen S, Halberg P, Ullman S, Hoier-Madsen M, Petersen J, Mortensen J, et al. A longitudinal study of pulmonary function in Danish patients with systemic sclerosis. Clin Rheumatol. 1997;16:384–90.CrossRefPubMed Jacobsen S, Halberg P, Ullman S, Hoier-Madsen M, Petersen J, Mortensen J, et al. A longitudinal study of pulmonary function in Danish patients with systemic sclerosis. Clin Rheumatol. 1997;16:384–90.CrossRefPubMed
8.
go back to reference Kahaleh B. Vascular disease in scleroderma: mechanisms of vascular injury. Rheum Dis Clin North Am. 2008;34:57–71.CrossRefPubMed Kahaleh B. Vascular disease in scleroderma: mechanisms of vascular injury. Rheum Dis Clin North Am. 2008;34:57–71.CrossRefPubMed
9.
go back to reference Koch AE, Distler O. Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther. 2007;9(2):S3.CrossRefPubMedPubMedCentral Koch AE, Distler O. Vasculopathy and disordered angiogenesis in selected rheumatic diseases: rheumatoid arthritis and systemic sclerosis. Arthritis Res Ther. 2007;9(2):S3.CrossRefPubMedPubMedCentral
10.
go back to reference VanWijk MJ, VanBavel E, Sturk A, Nieuwland R. Microparticles in cardiovascular diseases. Cardiovasc Res. 2003;59:277–87.CrossRefPubMed VanWijk MJ, VanBavel E, Sturk A, Nieuwland R. Microparticles in cardiovascular diseases. Cardiovasc Res. 2003;59:277–87.CrossRefPubMed
11.
go back to reference Morel O, Morel N, Freyssinet JM, Toti F. Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses. Platelets. 2008;19:9–23.CrossRefPubMed Morel O, Morel N, Freyssinet JM, Toti F. Platelet microparticles and vascular cells interactions: a checkpoint between the haemostatic and thrombotic responses. Platelets. 2008;19:9–23.CrossRefPubMed
12.
go back to reference Iversen LV, Ullman S, Østergaard O, Nielsen CT, Halberg P, Karlsmark T, et al. Circulating microparticles and plasma levels of soluble e- and p-selectins in patients with systemic sclerosis. Scand J Rheumatol. 2013;42:473–82.CrossRefPubMed Iversen LV, Ullman S, Østergaard O, Nielsen CT, Halberg P, Karlsmark T, et al. Circulating microparticles and plasma levels of soluble e- and p-selectins in patients with systemic sclerosis. Scand J Rheumatol. 2013;42:473–82.CrossRefPubMed
13.
go back to reference Subcommittee for scleroderma criteria of the American Rheumatism Association. Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23:581–90.CrossRef Subcommittee for scleroderma criteria of the American Rheumatism Association. Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980;23:581–90.CrossRef
14.
go back to reference LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger Jr TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202–5.PubMed LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger Jr TA, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988;15:202–5.PubMed
15.
go back to reference Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995;22:1281–5.PubMed Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995;22:1281–5.PubMed
16.
go back to reference MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26:720–35.CrossRefPubMed MacIntyre N, Crapo RO, Viegi G, Johnson DC, van der Grinten CPM, Brusasco V, et al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur Respir J. 2005;26:720–35.CrossRefPubMed
17.
go back to reference Standardized lung function testing. Report working party. Bull Eur Physiopathol Respir. (Suppl. 5): 1983:19;1-95. PMID: 6616097. Standardized lung function testing. Report working party. Bull Eur Physiopathol Respir. (Suppl. 5): 1983:19;1-95. PMID: 6616097.
18.
go back to reference Allanore Y, Borderie D, Meune C, Cabanes L, Weber S, Ekindjian OG, et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis Rheum. 2003;48:3503–8.CrossRefPubMed Allanore Y, Borderie D, Meune C, Cabanes L, Weber S, Ekindjian OG, et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers. Arthritis Rheum. 2003;48:3503–8.CrossRefPubMed
19.
go back to reference Nielsen CT, Østergaard O, Johnsen C, Jacobsen S, Heegaard NH. Distinct features of circulating microparticles and their relationship to clinical manifestations in systemic lupus erythematosus. Arthritis Rheum. 2011;63:3067–77.CrossRefPubMed Nielsen CT, Østergaard O, Johnsen C, Jacobsen S, Heegaard NH. Distinct features of circulating microparticles and their relationship to clinical manifestations in systemic lupus erythematosus. Arthritis Rheum. 2011;63:3067–77.CrossRefPubMed
20.
go back to reference Iversen LV, Østergaard O, Nielsen CT, Jacobsen S, Heegaard NH. A heparin-based method for flow cytometric analysis of microparticles directly from platelet-poor plasma in calcium containing buffer. J Immunol Methods. 2013;388:49–59.CrossRefPubMed Iversen LV, Østergaard O, Nielsen CT, Jacobsen S, Heegaard NH. A heparin-based method for flow cytometric analysis of microparticles directly from platelet-poor plasma in calcium containing buffer. J Immunol Methods. 2013;388:49–59.CrossRefPubMed
21.
go back to reference Cerinic MM, Valentini G, Sorano GG, D'Angelo S, Cuomo G, Fenu L, et al. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum. 2003;32:285–95.CrossRefPubMed Cerinic MM, Valentini G, Sorano GG, D'Angelo S, Cuomo G, Fenu L, et al. Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis. Semin Arthritis Rheum. 2003;32:285–95.CrossRefPubMed
22.
go back to reference Blann AD, Constans J, Carpentier P, Renard M, Satger B, Guerin V, et al. Soluble P selectin in systemic sclerosis: relationship with von Willebrand factor, autoantibodies and diffuse or localised/limited disease. Thromb Res. 2003;109:203–6.CrossRefPubMed Blann AD, Constans J, Carpentier P, Renard M, Satger B, Guerin V, et al. Soluble P selectin in systemic sclerosis: relationship with von Willebrand factor, autoantibodies and diffuse or localised/limited disease. Thromb Res. 2003;109:203–6.CrossRefPubMed
23.
go back to reference Nomura S, Inami N, Ozaki Y, Kagawa H, Fukuhara S. Significance of microparticles in progressive systemic sclerosis with interstitial pneumonia. Platelets. 2008;19:192–8.CrossRefPubMed Nomura S, Inami N, Ozaki Y, Kagawa H, Fukuhara S. Significance of microparticles in progressive systemic sclerosis with interstitial pneumonia. Platelets. 2008;19:192–8.CrossRefPubMed
24.
go back to reference Southcott AM, Hemingway I, Lorimer S, Sugars K, Hellewell PG, Black CM, et al. Adhesion molecule expression in the lung: a comparison between normal and diffuse interstitial lung disease. Eur Respir J. 1998;11:91–8.CrossRefPubMed Southcott AM, Hemingway I, Lorimer S, Sugars K, Hellewell PG, Black CM, et al. Adhesion molecule expression in the lung: a comparison between normal and diffuse interstitial lung disease. Eur Respir J. 1998;11:91–8.CrossRefPubMed
25.
go back to reference Ostojić P, Damjanov N. Different clinical features in patients with limited and diffuse cutaneous systemic sclerosis. Clin Rheumatol. 2006;25:453–7.CrossRefPubMed Ostojić P, Damjanov N. Different clinical features in patients with limited and diffuse cutaneous systemic sclerosis. Clin Rheumatol. 2006;25:453–7.CrossRefPubMed
26.
go back to reference Khanna D, Clements PJ, Furst DE, Chon Y, Elashoff R, Roth MD, et al. Correlation of degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis. Arthritis Rheum. 2005;52:592–600.CrossRefPubMed Khanna D, Clements PJ, Furst DE, Chon Y, Elashoff R, Roth MD, et al. Correlation of degree of dyspnea with health-related quality of life, functional abilities, and diffusing capacity for carbon monoxide in patients with systemic sclerosis and active alveolitis. Arthritis Rheum. 2005;52:592–600.CrossRefPubMed
27.
go back to reference Fijnheer R, Frijns CJ, Korteweg J, Rommes H, Peters JH, Sixma JJ, et al. Origin of P-selectin as a plasma protein. Thromb Haemost. 1997;77:1081–5.PubMed Fijnheer R, Frijns CJ, Korteweg J, Rommes H, Peters JH, Sixma JJ, et al. Origin of P-selectin as a plasma protein. Thromb Haemost. 1997;77:1081–5.PubMed
28.
go back to reference Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, Tando Y, et al. Differences in the released endothelial microparticle subtypes between human pulmonary microvascular endothelial cells and aortic endothelial cells in vitro. Exp Lung Res. 2013;39:155–61.CrossRefPubMed Takahashi T, Kobayashi S, Fujino N, Suzuki T, Ota C, Tando Y, et al. Differences in the released endothelial microparticle subtypes between human pulmonary microvascular endothelial cells and aortic endothelial cells in vitro. Exp Lung Res. 2013;39:155–61.CrossRefPubMed
29.
go back to reference Kaloudi O, Miniati I, Alari S, Matucci-Cerinic M. Interstitial lung disease in systemic sclerosis. Intern Emerg Med. 2007;2:250–5.CrossRefPubMed Kaloudi O, Miniati I, Alari S, Matucci-Cerinic M. Interstitial lung disease in systemic sclerosis. Intern Emerg Med. 2007;2:250–5.CrossRefPubMed
30.
go back to reference Joop K, Berckmans RJ, Nieuwland R, Berkhout J, Romijn FP, Hack CE, et al. Microparticles from patients with multiple organ dysfunction syndrome and sepsis support coagulation through multiple mechanisms. Thromb Haemost. 2001;85:810–20.PubMed Joop K, Berckmans RJ, Nieuwland R, Berkhout J, Romijn FP, Hack CE, et al. Microparticles from patients with multiple organ dysfunction syndrome and sepsis support coagulation through multiple mechanisms. Thromb Haemost. 2001;85:810–20.PubMed
31.
go back to reference Guiducci S, Distler JH, Jungel A, Huscher D, Huber LC, Michel BA, et al. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis. Arthritis Rheum. 2008;58:2845–53.CrossRefPubMed Guiducci S, Distler JH, Jungel A, Huscher D, Huber LC, Michel BA, et al. The relationship between plasma microparticles and disease manifestations in patients with systemic sclerosis. Arthritis Rheum. 2008;58:2845–53.CrossRefPubMed
32.
go back to reference Pamuk GE, Turgut B, Pamuk ON, Vural O, Demir M, Cakir N. Increased circulating platelet-leucocyte complexes in patients with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis: a comparative study. Blood Coagul Fibrinolysis. 2007;18:297–302.CrossRefPubMed Pamuk GE, Turgut B, Pamuk ON, Vural O, Demir M, Cakir N. Increased circulating platelet-leucocyte complexes in patients with primary Raynaud's phenomenon and Raynaud's phenomenon secondary to systemic sclerosis: a comparative study. Blood Coagul Fibrinolysis. 2007;18:297–302.CrossRefPubMed
33.
go back to reference Gashouta MA, Humbert M, Hassoun PM. Update in systemic sclerosis-associated pulmonary arterial hypertension. Presse Med. 2014;43:293–304.CrossRef Gashouta MA, Humbert M, Hassoun PM. Update in systemic sclerosis-associated pulmonary arterial hypertension. Presse Med. 2014;43:293–304.CrossRef
34.
go back to reference Gordon C, Gudi K, Krause A, Sackrowitz R, Harvey BG, Strulovici-Barel Y, et al. Circulating endothelial microparticles as a measure of early lung destruction in cigarette smokers. Am J Respir Crit Care Med. 2011;184:224–32.CrossRefPubMedPubMedCentral Gordon C, Gudi K, Krause A, Sackrowitz R, Harvey BG, Strulovici-Barel Y, et al. Circulating endothelial microparticles as a measure of early lung destruction in cigarette smokers. Am J Respir Crit Care Med. 2011;184:224–32.CrossRefPubMedPubMedCentral
35.
go back to reference McVey M, Tabuchi A, Kuebler WM. Microparticles and Acute Lung Injury. Am J Physiol Lung Cell Mol Physiol. 2012;303:364–81.CrossRef McVey M, Tabuchi A, Kuebler WM. Microparticles and Acute Lung Injury. Am J Physiol Lung Cell Mol Physiol. 2012;303:364–81.CrossRef
36.
go back to reference Hoogen F, Khanna D, Fransen J, Johnson JS, Baron M, Tyndall A, et al. Classification criteria for systemic sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum. 2013;65:2737–47.CrossRefPubMedPubMedCentral Hoogen F, Khanna D, Fransen J, Johnson JS, Baron M, Tyndall A, et al. Classification criteria for systemic sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum. 2013;65:2737–47.CrossRefPubMedPubMedCentral
37.
go back to reference Alhajeri H, Hudson M, Fritzler M, Pope J, Tatibouet S, Markland J, et al. 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis outperform the 1980 criteria: Data From the Canadian Scleroderma Research Group. Arthritis Care Res. 2015;67:582–7.CrossRef Alhajeri H, Hudson M, Fritzler M, Pope J, Tatibouet S, Markland J, et al. 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis outperform the 1980 criteria: Data From the Canadian Scleroderma Research Group. Arthritis Care Res. 2015;67:582–7.CrossRef
38.
go back to reference Connor DE, Exner T, Ma DD, Joseph JE. The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb Haemost. 2010;103:1044–52.CrossRefPubMed Connor DE, Exner T, Ma DD, Joseph JE. The majority of circulating platelet-derived microparticles fail to bind annexin V, lack phospholipid-dependent procoagulant activity and demonstrate greater expression of glycoprotein Ib. Thromb Haemost. 2010;103:1044–52.CrossRefPubMed
Metadata
Title
Cross-sectional study of soluble selectins, fractions of circulating microparticles and their relationship to lung and skin involvement in systemic sclerosis
Authors
Line V. Iversen
Susanne Ullman
Ole Østergaard
Christoffer T. Nielsen
Poul Halberg
Tonny Karlsmark
Niels H.H. Heegaard
Søren Jacobsen
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2015
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-015-0653-8

Other articles of this Issue 1/2015

BMC Musculoskeletal Disorders 1/2015 Go to the issue