Identification of a unique temporal signature in blood and BAL associated with IPF progression.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
21 07 2020
21 07 2020
Historique:
received:
17
01
2020
accepted:
18
05
2020
entrez:
23
7
2020
pubmed:
23
7
2020
medline:
18
12
2020
Statut:
epublish
Résumé
Idiopathic pulmonary fibrosis (IPF) is a progressive and heterogeneous interstitial lung disease of unknown origin with a low survival rate. There are few treatment options available due to the fact that mechanisms underlying disease progression are not well understood, likely because they arise from dysregulation of complex signaling networks spanning multiple tissue compartments. To better characterize these networks, we used systems-focused data-driven modeling approaches to identify cross-tissue compartment (blood and bronchoalveolar lavage) and temporal proteomic signatures that differentiated IPF progressors and non-progressors. Partial least squares discriminant analysis identified a signature of 54 baseline (week 0) blood and lung proteins that differentiated IPF progression status by the end of 80 weeks of follow-up with 100% cross-validation accuracy. Overall we observed heterogeneous protein expression patterns in progressors compared to more homogenous signatures in non-progressors, and found that non-progressors were enriched for proteomic processes involving regulation of the immune/defense response. We also identified a temporal signature of blood proteins that was significantly different at early and late progressor time points (p < 0.0001), but not present in non-progressors. Overall, this approach can be used to generate new hypothesis for mechanisms associated with IPF progression and could readily be translated to other complex and heterogeneous diseases.
Identifiants
pubmed: 32694604
doi: 10.1038/s41598-020-67956-w
pii: 10.1038/s41598-020-67956-w
pmc: PMC7374599
doi:
Substances chimiques
Biomarkers
0
Blood Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12049Subventions
Organisme : NHLBI NIH HHS
ID : K23 HL141539
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL139996
Pays : United States
Organisme : NHLBI NIH HHS
ID : L30 HL138825
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144849
Pays : United States
Organisme : NHLBI NIH HHS
ID : R35 HL144481
Pays : United States
Références
Lederer, D. J. & Martinez, F. J. Idiopathic pulmonary fibrosis. N. Engl. J. Med. 378, 1811–1823. https://doi.org/10.1056/NEJMra1705751 (2018).
doi: 10.1056/NEJMra1705751
pubmed: 29742380
Richeldi, L. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2071–2082. https://doi.org/10.1056/NEJMoa1402584 (2014).
doi: 10.1056/NEJMoa1402584
pubmed: 24836310
King, T. E. et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2083–2092. https://doi.org/10.1056/NEJMoa1402582 (2014).
doi: 10.1056/NEJMoa1402582
pubmed: 24836312
Lin, C., Borensztajn, K. & Spek, C. A. Targeting coagulation factor receptors—protease-activated receptors in idiopathic pulmonary fibrosis. J. Thromb. Haemost. 15, 597–607. https://doi.org/10.1111/jth.13623 (2017).
doi: 10.1111/jth.13623
pubmed: 28079978
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, 788–824. https://doi.org/10.1164/rccm.2009-040GL (2011).
doi: 10.1164/rccm.2009-040GL
pubmed: 21471066
pmcid: 5450933
Yusen, R. D. et al. The registry of the international society for heart and lung transplantation: thirty-third adult lung and heart-lung transplant report—2016; focus theme: primary diagnostic indications for transplant. J. Heart Lung Transpl. 35, 1170–1184. https://doi.org/10.1016/j.healun.2016.09.001 (2016).
doi: 10.1016/j.healun.2016.09.001
Jenkins, R. G. et al. Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study. Lancet Respir. Med. 3, 462–472. https://doi.org/10.1016/S2213-2600(15)00048-X (2015).
doi: 10.1016/S2213-2600(15)00048-X
pubmed: 25770676
Han, M. K. et al. Lung microbiome and disease progression in idiopathic pulmonary fibrosis: an analysis of the COMET study. Lancet Respir. Med. 2, 548–556. https://doi.org/10.1016/S2213-2600(14)70069-4 (2014).
doi: 10.1016/S2213-2600(14)70069-4
pubmed: 24767767
pmcid: 4142525
Chien, J. W. et al. Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression. Eur. Respir. J. 43, 1430–1438. https://doi.org/10.1183/09031936.00141013 (2014).
doi: 10.1183/09031936.00141013
pubmed: 24177001
Bouros, D. et al. Design, rationale, methodology, and aims of a Greek prospective idiopathic pulmonary fibrosis registry: investigating idiopathic pulmonary fibrosis in Greece (INDULGE IPF). Respiration 96, 41–47. https://doi.org/10.1159/000487244 (2018).
doi: 10.1159/000487244
pubmed: 29514162
Bauer, Y. et al. MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis. ERJ Open Res. 3, 00074–02016. https://doi.org/10.1183/23120541.00074-2016 (2017).
doi: 10.1183/23120541.00074-2016
pubmed: 28435843
pmcid: 5395293
Tzouvelekis, A. et al. Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology (Carlton,VIC) 22, 486–493. https://doi.org/10.1111/resp.12920 (2017).
doi: 10.1111/resp.12920
Prasse, A. et al. Serum CC-chemokine ligand 18 concentration predicts outcome in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 179, 717–723. https://doi.org/10.1164/rccm.200808-1201OC (2009).
doi: 10.1164/rccm.200808-1201OC
pubmed: 19179488
Barlo, N. P. et al. Surfactant protein-D predicts survival in patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc. Diffuse Lung Dis. 26, 155–161 (2009).
pubmed: 20560296
Takahashi, H. et al. Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent. Am. J. Respir. Crit. Care Med. 162, 1109–1114. https://doi.org/10.1164/ajrccm.162.3.9910080 (2000).
doi: 10.1164/ajrccm.162.3.9910080
pubmed: 10988138
Hamai, K. et al. Comparative study of circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as disease markers of idiopathic pulmonary fibrosis. Dis. Markers 1–8, 2016. https://doi.org/10.1155/2016/4759040 (2016).
doi: 10.1155/2016/4759040
Raghu, G. et al. Idiopathic pulmonary fibrosis: prospective, case-controlled study of natural history and circulating biomarkers. Chest 154, 1359–1370. https://doi.org/10.1016/J.CHEST.2018.08.1083 (2018).
doi: 10.1016/J.CHEST.2018.08.1083
pubmed: 30526970
Drakopanagiotakis, F., Wujak, L., Wygrecka, M. & Markart, P. Biomarkers in idiopathic pulmonary fibrosis. Matrix Biol. 68–69, 404–421. https://doi.org/10.1016/J.MATBIO.2018.01.023 (2018).
doi: 10.1016/J.MATBIO.2018.01.023
pubmed: 29408012
Pleasants, R. & Tighe, R. M. Management of idiopathic pulmonary fibrosis. Ann. Pharmacother. 53, 1238–1248. https://doi.org/10.1177/1060028019862497 (2019).
doi: 10.1177/1060028019862497
pubmed: 31280590
pmcid: 6745766
Ashley, S. L. et al. Six-SOMAmer index relating to immune, protease and angiogenic functions predicts progression in IPF. PLoS ONE 11, e0159878. https://doi.org/10.1371/journal.pone.0159878 (2016).
doi: 10.1371/journal.pone.0159878
pubmed: 27490795
pmcid: 4973878
Richards, T. J. et al. Peripheral blood proteins predict mortality in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 185, 67–76. https://doi.org/10.1164/rccm.201101-0058OC (2012).
doi: 10.1164/rccm.201101-0058OC
pubmed: 22016448
pmcid: 3262037
Todd, J. L. et al. Peripheral blood proteomic profiling of idiopathic pulmonary fibrosis biomarkers in the multicentre IPF-PRO registry. Respir. Res. 20, 227. https://doi.org/10.1186/s12931-019-1190-z (2019).
doi: 10.1186/s12931-019-1190-z
pubmed: 31640794
pmcid: 6805665
Maher, T. M. et al. An epithelial biomarker signature for idiopathic pulmonary fibrosis: an analysis from the multicentre PROFILE cohort study. Lancet Respir. Med. 5, 946–955. https://doi.org/10.1016/S2213-2600(17)30430-7 (2017).
doi: 10.1016/S2213-2600(17)30430-7
pubmed: 29150411
Bafadhel, M. et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am. J. Respir. Crit. Care Med. 184, 662–671. https://doi.org/10.1164/rccm.201104-0597OC (2011).
doi: 10.1164/rccm.201104-0597OC
pubmed: 21680942
Arnold, K. B. et al. Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of proteases, mucosal barrier proteins, and an influx of HIV-susceptible target cells. Mucosal Immunol. 9, 194–205. https://doi.org/10.1038/mi.2015.51 (2016).
doi: 10.1038/mi.2015.51
pubmed: 26104913
O’Dwyer, D. N. et al. The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes. Sci. Rep. 7, 46560. https://doi.org/10.1038/srep46560 (2017).
doi: 10.1038/srep46560
pubmed: 28440314
pmcid: 5404506
Norman, K. C. et al. Inference of cellular immune environments in sputum and peripheral blood associated with acute exacerbations of COPD. Cell. Mol. Bioeng. 12, 165–177. https://doi.org/10.1007/s12195-019-00567-2 (2019).
doi: 10.1007/s12195-019-00567-2
pubmed: 31719907
pmcid: 6816611
Tibshirani, R. Regression shrinkage and selection via the lasso. J. R. Stat. Soc. B 58, 267–288 (1994).
Lau, K. S. et al. In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-α-induced apoptosis and proliferation by MAPKs. Sci. Signal. 4, ra16. https://doi.org/10.1126/scisignal.2001338 (2011).
doi: 10.1126/scisignal.2001338
pubmed: 21427409
pmcid: 3963028
Jaffar, J. et al. Fibulin-1 predicts disease progression in patients with idiopathic pulmonary fibrosis. Chest 146, 1055–1063. https://doi.org/10.1378/chest.13-2688 (2014).
doi: 10.1378/chest.13-2688
pubmed: 24832167
pmcid: 4188142
Song, J. W. et al. Blood biomarkers MMP-7 and SP-A: predictors of outcome in idiopathic pulmonary fibrosis. Chest 143, 1422–1429. https://doi.org/10.1378/chest.11-2735 (2013).
doi: 10.1378/chest.11-2735
pubmed: 23715088
Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57. https://doi.org/10.1038/nprot.2008.211 (2009).
doi: 10.1038/nprot.2008.211
Beckwith-Hall, B. M. et al. Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. Chem. Res. Toxicol. 11, 260–272. https://doi.org/10.1021/TX9700679 (1998).
doi: 10.1021/TX9700679
pubmed: 9548796
Rosas, I. O. et al. MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis. PLoS Med 5, e93. https://doi.org/10.1371/journal.pmed.0050093 (2008).
doi: 10.1371/journal.pmed.0050093
pubmed: 2346504
pmcid: 2346504
Sahu, A. & Lambris, J. D. Structure and biology of complement protein C3, a connecting link between innate and acquired immunity. Immunol. Rev. 180, 35–48 (2001).
doi: 10.1034/j.1600-065X.2001.1800103.x
Foley, J. H. et al. Interplay between fibrinolysis and complement: Plasmin cleavage of iC3b modulates immune responses. J. Thromb. Haemost. 13, 610–618. https://doi.org/10.1111/jth.12837 (2015).
doi: 10.1111/jth.12837
pubmed: 25556624
Okamoto, T. et al. The relationship between complement C3 expression and the MUC5B genotype in pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 315, L1–L10. https://doi.org/10.1152/ajplung.00395.2017 (2018).
doi: 10.1152/ajplung.00395.2017
pubmed: 29565179
pmcid: 6087895
Phan, S. H. & Thrall, R. S. Inhibition of bleomycin-induced pulmonary fibrosis by cobra venom factor. Am. J. Pathol. 107, 25–28 (1982).
pubmed: 6175222
pmcid: 1915983
Glmnet for Matlab (2013) Qian, J., Hastie, T., Friedman, J., Tibshirani, R. and Simon, N. http://www.stanford.edu/~hastie/glmnet_matlab/ .