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Selection of AECOPD-specific immunomodulatory biomarkers by integrating genomics and proteomics with clinical informatics

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Abstract

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) as a serious event has high mortality and medical costs. Systemic inflammation and immune response are the major factors influencing the outcome and quality of patient with AECOPD. On basis of identification and validation of AECOPD-specific inflammatory biomarkers, the present study aimed to identify AECOPD-specific immunomodulatory mediators by evaluating dynamic genomic and proteomic profiles of peripheral blood mononuclear cells (PBMCs) and plasma in patients with AECOPD on day 1, 3, and 10 after the hospital admission, to compare with healthy controls or patients with stable COPD. We found that genes and proteins of C1QC and C1RL were co-differentially up-expressed in patients with COPD or AECOPD, while haptoglobin (HP), ORM1, SERPING1, and C3 were identified as a panel of AECOPD-specific immunomodulatory mediators. We also found that inflammatory stimuli could up-regulate osteopontin (OPN)-associated HP expression through the PI3K signal pathway in A549 cells. Block of autocrine production of OPN by gene inhibition could reduce HP production from inflammation-induced lung epithelial cells. The complex network of AECOPD- or COPD-specific immunomodulatory mediators will benefit the development of precision or personalized medicine strategies for prevention and treatment of AECOPD.

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References

  • Ashkar S, Weber GF, Panoutsakopoulou V, Sanchirico ME, Jansson M, Zawaideh S, et al. Eta-1 (osteopontin): an early component of type-1 (cell-mediated) immunity. Science. 2000;287(5454):860–4.

    Article  CAS  PubMed  Google Scholar 

  • Barnes PJ. Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin Chest Med. 2014;35(1):71–86.

    Article  PubMed  Google Scholar 

  • Barnes PJ, Shapiro SD, Pauwels RA. Chronic obstructive pulmonary disease: molecular and cellular mechanisms. The European respiratory journal : official journal of the European Society for Clinical Respiratory. Physiology. 2003;22(4):672–88.

    CAS  Google Scholar 

  • Beckman G, Eklund A, Frohlander N, Stjernberg N. Haptoglobin groups and lung cancer. Hum Hered. 1986;36(4):258–60.

    Article  CAS  PubMed  Google Scholar 

  • Bhattacharya S, Tyagi S, Srisuma S, Demeo DL, Shapiro SD, Bueno R, et al. Peripheral blood gene expression profiles in COPD subjects. Journal of clinical bioinformatics. 2011;1(1):12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bon JM, Leader JK, Weissfeld JL, Coxson HO, Zheng B, Branch RA, et al. The influence of radiographic phenotype and smoking status on peripheral blood biomarker patterns in chronic obstructive pulmonary disease. PLoS One. 2009;4(8):e6865.

    Article  PubMed  PubMed Central  Google Scholar 

  • Celli BR, Barnes PJ. Exacerbations of chronic obstructive pulmonary disease. The European respiratory journal: official journal of the European Society for Clinical Respiratory. Physiology. 2007;29(6):1224–38.

    CAS  Google Scholar 

  • Celli BR, Mac Nee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. The European respiratory journal: official journal of the European Society for Clinical Respiratory. Physiology. 2004;23(6):932–46.

    CAS  Google Scholar 

  • Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, et al. The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science. 2001;294(5547):1731–5.

    Article  CAS  PubMed  Google Scholar 

  • Chen C, Fang X, Wang Y, Li Y, Wang D, Zhao X, et al. Preventive and therapeutic effects of phosphoinositide 3-kinase inhibitors on acute lung injury. Chest. 2011;140(2):391–400.

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Song Z, Qian M, Bai C, Wang X. Selection of disease-specific biomarkers by integrating inflammatory mediators with clinical informatics in AECOPD patients: a preliminary study. J Cell Mol Med. 2012a;16(6):1286–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H, Wang D, Bai C, Wang X. Proteomics-based biomarkers in chronic obstructive pulmonary disease. J Proteome Res. 2010;9(6):2798–808.

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Wang X. Significance of bioinformatics in research of chronic obstructive pulmonary disease. Journal of clinical bioinformatics. 2011;1:35.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen H, Wang Y, Bai C, Wang X. Alterations of plasma inflammatory biomarkers in the healthy and chronic obstructive pulmonary disease patients with or without acute exacerbation. J Proteome. 2012b;75(10):2835–43.

    Article  CAS  Google Scholar 

  • Cid MC, Grant DS, Hoffman GS, Auerbach R, Fauci AS, Kleinman HK. Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J Clin Invest. 1993;91(3):977–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de Torres JP, Casanova C, Pinto-Plata V, Varo N, Restituto P, Cordoba-Lanus E, et al. Gender differences in plasma biomarker levels in a cohort of COPD patients: a pilot study. PLoS One. 2011;6(1):e16021.

    Article  PubMed  PubMed Central  Google Scholar 

  • Denhardt DT, Noda M, O'Regan AW, Pavlin D, Berman JS. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest. 2001;107(9):1055–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang X, Li K, Tao X, Chen C, Wang X, Wang L, et al. Effects of phosphoinositide 3-kinase on protease-induced acute and chronic lung inflammation, remodeling, and emphysema in rats. Chest. 2013a;143(4):1025–35.

    Article  CAS  PubMed  Google Scholar 

  • Fang X, Netzer M, Baumgartner C, Bai C, Wang X. Genetic network and gene set enrichment analysis to identify biomarkers related to cigarette smoking and lung cancer. Cancer Treat Rev. 2013b;39(1):77–88.

    Article  CAS  PubMed  Google Scholar 

  • Fang X, Wang X, Bai C. COPD in China: the burden and importance of proper management. Chest. 2011;139(4):920–9.

    Article  PubMed  Google Scholar 

  • Guirguis-Blake JM, Senger CA, Webber EM, Mularski RA, Whitlock EP. Screening for chronic obstructive pulmonary disease: evidence report and systematic review for the US preventive services task force. JAMA. 2016;315(13):1378–93.

    Article  CAS  PubMed  Google Scholar 

  • Gutteridge JM. The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta. 1987;917(2):219–23.

    Article  CAS  PubMed  Google Scholar 

  • He Z, Chen Y, Chen P, Wu G, Cai S. Local inflammation occurs before systemic inflammation in patients with COPD. Respirology. 2010;15(3):478–84.

    Article  PubMed  Google Scholar 

  • Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med. 2004;350(26):2645–53.

    Article  CAS  PubMed  Google Scholar 

  • Huntoon KM, Russell L, Tracy E, Barbour KW, Li Q, Shrikant PA, et al. A unique form of haptoglobin produced by murine hematopoietic cells supports B-cell survival, differentiation and immune response. Mol Immunol. 2013;55(3–4):345–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khazaei HA, Nakhaei A, Dashti GA, Mohammadi M, Hejazenia F, Mehrangeez N, et al. Association of haptoglobin phenotypes with serum levels of IgE and IgA in allergic rhinitis patients. Iranian journal of immunology: IJI. 2012;9(4):254–60.

    PubMed  Google Scholar 

  • Landi C, Bargagli E, Magi B, Prasse A, Muller-Quernheim J, Bini L, et al. Proteome analysis of bronchoalveolar lavage in pulmonary langerhans cell histiocytosis. Journal of clinical bioinformatics. 2011;1:31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem. 1996;42(10):1589–600.

    CAS  PubMed  Google Scholar 

  • Larsen K, Macleod D, Nihlberg K, Gurcan E, Bjermer L, Marko-Varga G, et al. Specific haptoglobin expression in bronchoalveolar lavage during differentiation of circulating fibroblast progenitor cells in mild asthma. J Proteome Res. 2006;5(6):1479–83.

    Article  CAS  PubMed  Google Scholar 

  • Lin YH, Yang-Yen HF. The osteopontin-CD44 survival signal involves activation of the phosphatidylinositol 3-kinase/Akt signaling pathway. J Biol Chem. 2001;276(49):46024–30.

    Article  CAS  PubMed  Google Scholar 

  • Liu R, Wang X, Aihara K, Chen L. Early diagnosis of complex diseases by molecular biomarkers, network biomarkers, and dynamical network biomarkers. Med Res Rev. 2014;34(3):455–78.

    Article  PubMed  Google Scholar 

  • Mac Beath G. Protein microarrays and proteomics. Nat Genet. 2002;32(Suppl):526–32.

    Article  CAS  Google Scholar 

  • Melguizo C, Prados J, Luque R, Ortiz R, Rama AR, Caba O, et al. Modulation of multidrug resistance gene expression in peripheral blood mononuclear cells of lung cancer patients and evaluation of their clinical significance. Cancer Chemother Pharmacol. 2013;71(2):537–41.

    Article  CAS  PubMed  Google Scholar 

  • Murtagh E, Heaney L, Gingles J, Shepherd R, Kee F, Patterson C, et al. Prevalence of obstructive lung disease in a general population sample: the NICECOPD study. Eur J Epidemiol. 2005;20(5):443–53.

    Article  PubMed  Google Scholar 

  • Niu F, Wang DC, Lu J, Wu W, Wang X. Potentials of single-cell biology in identification and validation of disease biomarkers. J Cell Mol Med. 2016; doi:10.1111/jcmm.12868.

  • Oh SK, Pavlotsky N, Tauber AI. Specific binding of haptoglobin to human neutrophils and its functional consequences. J Leukoc Biol. 1990;47(2):142–8.

    Article  CAS  PubMed  Google Scholar 

  • Okamoto T, Miyazaki Y, Shirahama R, Tamaoka M, Inase N. Proteome analysis of bronchoalveolar lavage fluid in chronic hypersensitivity pneumonitis. Allergology international: official journal of the Japanese Society of Allergology. 2012;61(1):83–92.

    Article  CAS  Google Scholar 

  • Philip S, Kundu GC. Osteopontin induces nuclear factor kappa B-mediated promatrix metalloproteinase-2 activation through I kappa B alpha/IKK signaling pathways, and curcumin (diferulolylmethane) down-regulates these pathways. J Biol Chem. 2003;278(16):14487–97.

    Article  CAS  PubMed  Google Scholar 

  • Prins HJ, Daniels JM, Lindeman JH, Lutter R, Boersma WG. Effects of doxycycline on local and systemic inflammation in stable COPD patients, a randomized clinical trial. Respir Med. 2016;110:46–52.

    Article  PubMed  Google Scholar 

  • Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest. 2000;117(5 Suppl 2):398S–401S.

    Article  CAS  PubMed  Google Scholar 

  • Rubinsztajn R, Przybylowski T, Maskey-Warzechowska M, Karwat K, Chazan R. Exacerbations of chronic obstructive pulmonary disease and quality of life of patients. Adv Exp Med Biol. 2016;884:69–74.

    Article  CAS  PubMed  Google Scholar 

  • Rupp J, Kothe H, Mueller A, Maass M, Dalhoff K. Imbalanced secretion of IL-1beta and IL-1RA in chlamydia pneumoniae-infected mononuclear cells from COPD patients. The European respiratory journal: official journal of the European Society for Clinical Respiratory. Physiology. 2003;22(2):274–9.

    CAS  Google Scholar 

  • Salvatore A, Cigliano L, Bucci EM, Corpillo D, Velasco S, Carlucci A, et al. Haptoglobin binding to apolipoprotein A-I prevents damage from hydroxyl radicals on its stimulatory activity of the enzyme lecithin-cholesterol acyl-transferase. Biochemistry. 2007;46(39):11158–68.

    Article  CAS  PubMed  Google Scholar 

  • Thorleifsson SJ, Margretardottir OB, Gudmundsson G, Olafsson I, Benediktsdottir B, Janson C, et al. Chronic airflow obstruction and markers of systemic inflammation: results from the BOLD study in Iceland. Respir Med. 2009;103(10):1548–53.

    Article  PubMed  PubMed Central  Google Scholar 

  • Valipour A, Schreder M, Wolzt M, Saliba S, Kapiotis S, Eickhoff P, et al. Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease. Clin Sci (Lond). 2008;115(7):225–32.

    Article  CAS  Google Scholar 

  • Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2013;187(4):347–65.

    Article  CAS  PubMed  Google Scholar 

  • Wai PY, Kuo PC. The role of Osteopontin in tumor metastasis. J Surg Res. 2004;121(2):228–41.

    Article  CAS  PubMed  Google Scholar 

  • Wang KX, Denhardt DT. Osteopontin: role in immune regulation and stress responses. Cytokine Growth Factor Rev. 2008;19(5–6):333–45.

    Article  CAS  PubMed  Google Scholar 

  • Wang X. Role of clinical bioinformatics in the development of network-based biomarkers. Journal of clinical bioinformatics. 2011;1(1):28.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang X, Adler KB, Erjefalt J, Bai C. Airway epithelial dysfunction in the development of acute lung injury and acute respiratory distress syndrome. Expert review of respiratory medicine. 2007;1(1):149–55.

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Ward PA. Opportunities and challenges of disease biomarkers: a new section in the journal of translational medicine. J Transl Med. 2012;10:240.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wen CL, Chen KY, Chen CT, Chuang JG, Yang PC, Chow LP. Development of an alpha LISA assay to quantify serum core-fucosylated E-cadherin as a metastatic lung adenocarcinoma biomarker. J Proteome. 2012;75(13):3963–76.

    Article  CAS  Google Scholar 

  • Wu X, Chen L, Wang X. Network biomarkers, interaction networks and dynamical network biomarkers in respiratory diseases. Clinical and translational medicine. 2014a;3:16.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wu X, Sun X, Chen C, Bai C, Wang X. Dynamic gene expressions of peripheral blood mononuclear cells in patients with acute exacerbation of chronic obstructive pulmonary disease: a preliminary study. Crit Care. 2014b;18(6):508.

    Article  PubMed  PubMed Central  Google Scholar 

  • Xie Y, Li Y, Kong Y. OPN induces fox M1 expression and localization through ERK 1/2, AKT, and p38 signaling pathway in HEC-1A cells. Int J Mol Sci. 2014;15(12):23345–58.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhao C, Annamalai L, Guo C, Kothandaraman N, Koh SC, Zhang H, et al. Circulating haptoglobin is an independent prognostic factor in the sera of patients with epithelial ovarian cancer. Neoplasia. 2007;9(1):1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao W, Wang L, Zhang L, Yuan C, Kuo PC, Gao C. Differential expression of intracellular and secreted osteopontin isoforms by murine macrophages in response to toll-like receptor agonists. J Biol Chem. 2010;285(27):20452–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work was supported by Shanghai Leading Academic Discipline Project (B115), Zhongshan Distinguished Professor Grant (XDW), the National Nature Science Foundation of China (91230204, 81270099, 81320108001, 81270131, 81400035, 81570075, 81500058, 81500025), the Shanghai Committee of Science and Technology (12JC1402200, 12431900207, 11410708600), Zhejiang Provincial Natural Science Foundation (LZ15H010001), and Zhejiang Provincial Science Technology Department Foundation (WKJ-ZJ-1526).

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  1. Zhongshan Hospital Institute of Clinical Science, Shanghai Institute of Clinical Bioinformatics, Shanghai Medical College, Fudan University, Shanghai, China

    Lin Shi, Bijun Zhu, Menglin Xu & Xiangdong Wang

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  1. Lin Shi
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  2. Bijun Zhu
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  3. Menglin Xu
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  4. Xiangdong Wang
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Conceived and designed the study: Xiangdong Wang; performed the biological experiments: Lin Shi; statistical analysis: Bijun Zhu and Menglin Xu. Wrote the paper: Lin Shi. All authors read and proofed the final manuscript.

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Correspondence to Xiangdong Wang.

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Shi, L., Zhu, B., Xu, M. et al. Selection of AECOPD-specific immunomodulatory biomarkers by integrating genomics and proteomics with clinical informatics. Cell Biol Toxicol 34, 109–123 (2018). https://doi.org/10.1007/s10565-017-9405-x

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