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Open Access 01-12-2018 | Research

A Serological Biomarker of Versican Degradation is Associated with Mortality Following Acute Exacerbations of Idiopathic Interstitial Pneumonia

Authors: Jannie M. B. Sand, Yoshinori Tanino, Morten A. Karsdal, Takefumi Nikaido, Kenichi Misa, Yuki Sato, Ryuichi Togawa, Xintao Wang, Diana J. Leeming, Mitsuru Munakata

Published in: Respiratory Research | Issue 1/2018

Abstract

Background

Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis. Acute exacerbations of IIP represent periods of increased disease activity, thus we hypothesized that ECM remodeling was altered during acute exacerbations and investigated this by serological neo-epitope biomarkers.

Methods

Patients who were sequentially admitted to the hospital with acute exacerbations of IIP were retrospectively analyzed for ECM remodeling at time of exacerbation (AE-IIP) and at clinical stability (S-IIP). Biomarkers released by matrix metalloproteinase-mediated degradation of collagen type I (C1M), III (C3M), IV (C4M), and VI (C6M), elastin (ELM7), versican (VCANM), biglycan (BGM), and C-reactive protein (CRPM) were assessed in serum by competitive ELISAs utilizing neo-epitope specific monoclonal antibodies.

Results

Sixty-eight patients at AE-IIP and 29 at S-IIP were included in this retrospective analysis. Of these, 28 and 11 patients, respectively, had idiopathic pulmonary fibrosis. At AE-IIP, serum levels of C4M (p = 0.002) and C6M (p = 0.024) were increased as compared with S-IIP, while ELM7 (p = 0.024) and VCANM (p < 0.0001) were decreased. Lower VCANM levels at AE-IIP were associated with increased risk of mortality (HR 0.64 [95% CI 0.43–0.94], p = 0.022).

Conclusions

The ECM remodeling profile was significantly altered during acute exacerbations of IIP, and a biomarker of versican degradation was related to mortality outcome. These results indicate that biomarkers of ECM remodeling may be useful in the non-invasive evaluation of acute exacerbations of IIP. Especially versican degradation, as measured serologically by VCANM, may have prognostic potential and help guide treatment for acute exacerbations.

Travis WD, Costabel U, Hansell DM, King TE, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188:733–48. https://doi.org/10.1164/rccm.201308-1483ST.CrossRefPubMedPubMedCentral

Daccord C, Maher TM. Recent advances in understanding idiopathic pulmonary fibrosis. F1000Research. 2016;5:1–13. https://doi.org/10.12688/f1000research.8209.1.CrossRef

Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis an international working group report. Am J Respir Crit Care Med. 2016;194:265–75. https://doi.org/10.1164/rccm.201604-0801CI.CrossRefPubMed

Rockey DC, Bell PD, Hill JA. Fibrosis — a common pathway to organ injury and failure. N Engl J Med. 2015;372:1138–49. https://doi.org/10.1056/NEJMra1300575.CrossRefPubMed

Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–40. https://doi.org/10.1038/nm.2807.CrossRefPubMedPubMedCentral

Karsdal MA, Nielsen MJ, Sand JM, Henriksen K, Genovese F, Bay-Jensen A-C, et al. Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive structure, but a key player in tissue failure. Assay Drug Dev Technol. 2013;11:70–92. https://doi.org/10.1089/adt.2012.474.CrossRefPubMedPubMedCentral

Sand JMB, Knox AJ, Lange P, Sun S, Kristensen JH, Leeming DJ, et al. Accelerated extracellular matrix turnover during exacerbations of COPD. Respir Res. 2015;16:69. https://doi.org/10.1186/s12931-015-0225-3.CrossRefPubMedPubMedCentral

Stolz D, Leeming DJ, Kristensen JHE, Karsdal MA, Boersma W, Louis R, et al. Systemic biomarkers of collagen and elastin turnover are associated with clinically relevant outcomes in COPD. Chest. 2017;151:47–59. https://doi.org/10.1016/j.chest.2016.08.1440.CrossRefPubMed

Jenkins RG, Simpson JK, Saini G, Bentley JH, Russell AM, Braybrooke R, et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir Med. 2015;3:462–72. https://doi.org/10.1016/S2213-2600(15)00048-X.CrossRefPubMed

10.

Andersson-Sjöland A, Hallgren O, Rolandsson S, Weitoft M, Tykesson E, Larsson-Callerfelt AK, et al. Versican in inflammation and tissue remodeling: the impact on lung disorders. Glycobiology. 2015;25:243–51. https://doi.org/10.1093/glycob/cwu120.CrossRefPubMed

11.

Sgalla G, Biffi A, Richeldi L. Idiopathic pulmonary fibrosis: diagnosis, epidemiology and natural history. Respirology. 2016;21:427–37. https://doi.org/10.1111/resp.12683.CrossRefPubMed

12.

Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, 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. 2011;183:788–824. https://doi.org/10.1164/rccm.2009-040GL.CrossRefPubMedPubMedCentral

13.

Inokoshi Y, Tanino Y, Wang X, Sato S, Fukuhara N, Nikaido T, et al. Clinical significance of serum hyaluronan in chronic fibrotic interstitial pneumonia. Respirology. 2013;18:1236–43. https://doi.org/10.1111/resp.12144.CrossRefPubMed

14.

Leeming D, He Y, Veidal S, Nguyen Q, Larsen D, Koizumi M, et al. A novel marker for assessment of liver matrix remodeling: an enzyme-linked immunosorbent assay (ELISA) detecting a MMP generated type I collagen neo-epitope (C1M). Biomarkers. 2011;16:616–28. https://doi.org/10.3109/1354750X.2011.620628.CrossRefPubMed

15.

Veidal SS, Vassiliadis E, Barascuk N, Zhang C, Segovia-Silvestre T, Klickstein L, et al. Matrix metalloproteinase-9-mediated type III collagen degradation as a novel serological biochemical marker for liver fibrogenesis. Liver Int. 2010;30:1293–304. https://doi.org/10.1111/j.1478-3231.2010.02309.x.CrossRefPubMed

16.

Sand JM, Larsen L, Hogaboam C, Martinez F, Han M, Røssel Larsen M, et al. MMP mediated degradation of type IV collagen alpha 1 and alpha 3 chains reflects basement membrane remodeling in experimental and clinical fibrosis--validation of two novel biomarker assays. PLoS One. 2013;8:e84934. https://doi.org/10.1371/journal.pone.0084934.CrossRefPubMedPubMedCentral

17.

Veidal SS, Karsdal MA, Vassiliadis E, Nawrocki A, Larsen MR, Nguyen QHT, et al. MMP mediated degradation of type VI collagen is highly associated with liver fibrosis - identification and validation of a novel biochemical marker assay. PLoS One. 2011;6:1–9. https://doi.org/10.1371/journal.pone.0024753. CrossRef

18.

Kristensen JH, Larsen L, Dasgupta B, Brodmerkel C, Curran M, Karsdal MA, et al. Levels of circulating MMP-7 degraded elastin are elevated in pulmonary disorders. Clin Biochem. 2015;48:1083–8. https://doi.org/10.1016/j.clinbiochem.2015.07.009.CrossRefPubMed

19.

Genovese F, Barascuk N, Larsen L, Larsen MR, Nawrocki A, Li Y, et al. Biglycan fragmentation in pathologies associated with extracellular matrix remodeling by matrix metalloproteinases. Fibrogenesis Tissue Repair. 2013;6:9. https://doi.org/10.1186/1755-1536-6-9.CrossRefPubMedPubMedCentral

20.

Barascuk N, Genovese F, Larsen L, Byrjalsen I, Zheng Q, Sun S, et al. A MMP derived versican neo-epitope is elevated in plasma from patients with atherosclerotic heart disease. Int J Clin Exp Med. 2013;6:174–84.PubMedPubMedCentral

21.

Skjøt-Arkil H, Schett G, Zhang C, Larsen DV, Wang Y, Zheng Q, et al. Investigation of two novel biochemical markers of inflammation, matrix metalloproteinase and cathepsin generated fragments of C-reactive protein, in patients with ankylosing spondylitis. Clin Exp Rheumatol. 2012;30:371–9.PubMed

22.

Antoniou KM, Wells AU. Acute exacerbations of idiopathic pulmonary fibrosis. Respiration. 2013;86:265–74. https://doi.org/10.1159/000355485.CrossRefPubMed

23.

Collard HR, Calfee CS, Wolters PJ, Song JW, Hong S-B, Brady S, et al. Plasma biomarker profiles in acute exacerbation of idiopathic pulmonary fibrosis. AJP Lung Cell Mol Physiol. 2010;299:L3–7. https://doi.org/10.1152/ajplung.90637.2008.CrossRef

24.

Sato Y, Tanino Y, Wang X, Nikaido T, Sato S, Misa K, et al. Baseline serum syndecan-4 predicts prognosis after the onset of acute exacerbation of idiopathic interstitial pneumonia. PLoS One. 2017;12:1–16. https://doi.org/10.1371/journal.pone.0176789.

25.

Bensadoun ES, Burke AK, Hogg JC, Roberts CR. Proteoglycan deposition in pulmonary fibrosis. Am J Respir Crit Care Med. 1996;154:1819–28. https://doi.org/10.1164/ajrccm.154.6.8970376.CrossRefPubMed

26.

Estany S, Vicens-Zygmunt V, Llatjós R, Montes A, Penín R, Escobar I, et al. Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFβ1. BMC Pulm Med. 2014;14:120. https://doi.org/10.1186/1471-2466-14-120.CrossRefPubMedPubMedCentral

27.

Merrilees MJ, Ching PST, Beaumont B, Hinek A, Wight TN, Black PN. Changes in elastin, elastin binding protein and versican in alveoli in chronic obstructive pulmonary disease. Respir Res. 2008;9:41. https://doi.org/10.1186/1465-9921-9-41.CrossRefPubMedPubMedCentral

28.

Hallgren O, Nihlberg K, Dahlbäck M, Bjermer L, Eriksson LT, Erjefält JS, et al. Altered fibroblast proteoglycan production in COPD. Respir Res. 2010;11:55. https://doi.org/10.1186/1465-9921-11-55.CrossRefPubMedPubMedCentral

29.

Nihlberg K, Andersson-Sjoland A, Tufvesson E, Erjefalt JS, Bjermer L, Westergren-Thorsson G. Altered matrix production in the distal airways of individuals with asthma. Thorax. 2010;65:670–6. https://doi.org/10.1136/thx.2009.129320.CrossRefPubMed

30.

Huang R, Merrilees MJ, Braun K, Beaumont B, Lemire J, Clowes AW, et al. Inhibition of versican synthesis by antisense alters smooth muscle cell phenotype and induces elastic fiber formation in vitro and in neointima after vessel injury. Circ Res. 2006;98:370–7. https://doi.org/10.1161/01.RES.0000202051.28319.c8.CrossRefPubMed

31.

Chang MY, Tanino Y, Vidova V, Kinsella MG, Chan CK, Johnson PY, et al. Reprint of: a rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease. Matrix Biol. 2014;35:162–73. https://doi.org/10.1016/j.matbio.2014.04.003.CrossRefPubMedPubMedCentral

32.

Kang I, Harten IA, Chang MY, Braun KR, Sheih A, Nivison MP, et al. Versican deficiency significantly reduces lung inflammatory response induced by polyinosine-polycytidylic acidstimulation. J Biol Chem. 2017;292:51–63. https://doi.org/10.1109/JPHOT.2016.2639045. CrossRefPubMed

33.

Raghu G, Lynch D, Godwin JD, Webb R, Colby TV, Leslie KO, et al. Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial. Lancet Respir Med. 2014;2:277–84. https://doi.org/10.1016/S2213-2600(14)70011-6.CrossRefPubMed

34.

Chung JH, Chawla A, Peljto AL, Cool CD, Groshong SD, Talbert JL, et al. CT scan findings of probable usual interstitial pneumonitis have a high predictive value for histologic usual interstitial pneumonitis. Chest. 2015;147:450–9. https://doi.org/10.1378/chest.14-0976.CrossRefPubMed

35.

Brownell R, Moua T, Henry TS, Elicker BM, White D, Vittinghoff E, et al. The use of pretest probability increases the value of high-resolution CT in diagnosing usual interstitial pneumonia. Thorax. 2017;72:424–9. https://doi.org/10.1136/thoraxjnl-2016-209671.CrossRefPubMedPubMedCentral

Title: A Serological Biomarker of Versican Degradation is Associated with Mortality Following Acute Exacerbations of Idiopathic Interstitial Pneumonia
Authors: Jannie M. B. Sand
Yoshinori Tanino
Morten A. Karsdal
Takefumi Nikaido
Kenichi Misa
Yuki Sato
Ryuichi Togawa
Xintao Wang
Diana J. Leeming
Mitsuru Munakata
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Respiratory Research / Issue 1/2018
Electronic ISSN: 1465-993X
DOI: https://doi.org/10.1186/s12931-018-0779-y

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Methods

Results

Conclusions

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