Annexin A5 Protein as a Potential Biomarker for the Diagnosis of Asthma

Abstract

Purpose

Annexin A5 (ANXA5) has a potential role in cellular signal transduction, inflammation, and fibrosis. However, the exact role of ANXA5 in asthma remains to be clarified. The aims of the present study were to investigate ANXA5 protein expression in a mouse model of asthma and pollutant exposure and to elucidate the relationships between clinical variables and plasma ANXA5 levels in patients with asthma.

Methods

A murine model of asthma induced by ovalbumin (OVA) and titanium dioxide (TiO2) nanoparticles has been established using BALB/c mice, and we examined ANXA5 expression and lung fibrosis using this model. Moreover, we also compared ANXA5 plasma levels in patients with controlled vs. exacerbated asthma.

Results

ANXA5 protein levels were lower in lung tissue from OVA + OVA mice than in control mice. Lung ANXA5, connective tissue growth factor (CTGF), and transforming growth factor β1 (TGF-β1) protein levels were higher in OVA + TiO2-exposed mice than in control or OVA + OVA mice. Although Dermatophagoides pteronyssinus (Derp1) treatment increased lung ANXA5 protein levels in MRC-5 cells and A549 epithelial cells, it decreased lung ANXA5 levels in NHBE cells. Treatment with TiO2 nanoparticles increased lung ANXA5, CTGF, and TGF-β1 protein levels in MRC-5 cells, A549 epithelial cells, and NHBE cells. Plasma ANXA5 levels were lower in asthmatic patients than in healthy controls, and they were significantly enriched in patients with exacerbated asthma compared with those with controlled asthma (P < 0.05). ANXA5 levels were correlated with pulmonary function as assessed by spirometry.

Conclusion

Our results imply that ANXA5 plays a potential role in asthma pathogenesis and may be a promising marker for exacerbated bronchial asthma and exposure to air pollutants.

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References

  1. 1.

    Global Initiative for Asthma (GINA) (2016) Global strategy for asthma management and prevention. http://ginasthma.org/wp-content/uploads/2016/04/wms-GINA-2016-main-report-final.pdf

  2. 2.

    Berair R, Brightling CE (2014) Asthma therapy and its effect on airway remodeling. Drugs 74:1345–1369

    CAS  Article  Google Scholar 

  3. 3.

    Pavord ID, Afzalnia S, Menzies-Gow A, Heaney LG (2017) The current and future role of biomarkers in type 2 cytokine-mediated asthma management. Clin Exp Allergy 47:148–160

    CAS  Article  Google Scholar 

  4. 4.

    Chen Z, Yoshihara E, Son A, Matsuo Y, Masutani H, Sugie K et al (2010) Differential roles of Annexin A1 (ANXA1/lipocortin-1/lipomodulin) and thioredoxin binding protein-2 (TBP 2/VDUP1/TXNIP) in glucocorticoid signaling of HTLV-I-transformed T cells. Immunol Lett 131:11–18

    CAS  Article  Google Scholar 

  5. 5.

    Majeed M, Ernst JD, Magnusson KE, Kihlström E, Stendahl O (1994) Selective translocation of annexins III, IV, and V during intracellular redistribution of Chlamydia trachomatis serovar L2 in HeLa and McCoy cells. Ann N Y Acad Sci 730:326–328

    CAS  Article  Google Scholar 

  6. 6.

    Monastyrskaya K, Babiychuk EB, Draeger A (2009) The annexins: spatial and temporal coordination of signaling events during cellular stress. Cell Mol Life Sci 66:2623–2642

    CAS  Article  Google Scholar 

  7. 7.

    Tzima E, Poujol C, Nurden P, Nurden AT, Orchard MA, Walker JH (1999) Annexin V relocates to the periphery of activated platelets following thrombin activation: an ultrastructural immunohistochemical approach. Cell Biol Int 23:629–635

    CAS  Article  Google Scholar 

  8. 8.

    Ghislat G, Aguado C, Knecht E (2012) Annexin A5 stimulates autophagy and inhibits endocytosis. J Cell Sci 125:92–107

    CAS  Article  Google Scholar 

  9. 9.

    Rand JH, Wu XX, Lin EY, Griffel A, Gialanella P, McKitrick JC (2012) Annexin A5 binds to lipopolysaccharide and reduces its endotoxin activity. MBio 13(2):3

    Google Scholar 

  10. 10.

    Deng S, Wang J, Hou L, Li J, Chen G, Jing B et al (2013) Annexin A1, A2, A4 and A5 play important roles in breast cancer, pancreatic cancer and laryngeal carcinoma, alone and/or synergistically. Oncol Lett 5:107–112

    CAS  Article  Google Scholar 

  11. 11.

    Bouter A, Carmeille R, Gounou C, Bouvet F, Degrelle SA, Evain-Brion D et al (2015) Review: Annexin-A5 and cell membrane repair. Placenta 36(Suppl1):S43–S49

    CAS  Article  Google Scholar 

  12. 12.

    Luo C, Ji X, Fan J, Hou Z, Wang T, Wu B et al (2016) Annexin A5 promotes macrophage activation and contributes to pulmonary fibrosis induced by silica particles. Toxicol Ind Health 32:1628–1638

    CAS  Article  Google Scholar 

  13. 13.

    Yoshida S, Minematsu N, Chubachi S, Nakamura H, Miyazaki M, Tsuduki K et al (2012) Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 303:L852–L860

    CAS  Article  Google Scholar 

  14. 14.

    Bottcher A, Gaipl US, Furnrohr BG, Herrmann M, Girkontaite I, Kalden JR et al (2006) Involvement of phosphatidylserine, alphavbeta3, CD14, CD36, and complement C1q in the phagocytosis of primary necrotic lymphocytes by macrophages. Arthritis Rheum 54:927–938

    CAS  Article  Google Scholar 

  15. 15.

    Kenis H, van Genderen H, Deckers NM, Lux PA, Hofstra L, Narula J et al (2006) Annexin A5 inhibits engulfment through internalization of PS-expressing cell membrane patches. Exp Cell Res 312:719–726

    CAS  Article  Google Scholar 

  16. 16.

    Krahling S, Callahan MK, Williamson P, Schlegel RA (1999) Exposure of phosphatidylserine is a general feature in the phagocytosis of apoptotic lymphocytes by macrophages. Cell Death Differ 6:183–189

    CAS  Article  Google Scholar 

  17. 17.

    Boersma HH, Kietselaer BL, Stolk LM, Bennaghmouch A, Hofstra L, Narula J et al (2005) Past, present, and future of annexin A5: from protein discovery to clinical applications. J Nucl Med 46:2035–2050

    CAS  PubMed  Google Scholar 

  18. 18.

    Schutters K, Reutelingsperger C (2010) Phosphatidylserine targeting for diagnosis and treatment of human diseases. Apoptosis 15:1072–1082

    CAS  Article  Google Scholar 

  19. 19.

    Van Genderen HO, Kenis H, Hofstra L, Narula J, Reutelingsperger CP (2008) Extracellular annexin A5: functions of phosphatidylserine-binding and two-dimensional crystallization. Biochim Biophys Acta 1783:953–963

    Article  Google Scholar 

  20. 20.

    Raynal P, Pollard HB (1994) Annexins: the problem of assessing the biological role for a gene family of multifunctional calcium- and phospholipid-binding proteins. Biochim Biophys Acta 1197:63–93

    CAS  Article  Google Scholar 

  21. 21.

    Ewing MM, de Vries MR, Nordzell M, Pettersson K, de Boer HC, van Zonneveld AJ et al (2011) Annexin A5 therapy attenuates vascular inflammation and remodeling and improves endothelial function in mice. Arterioscler Thromb Vasc Biol 31:95–101

    CAS  Article  Google Scholar 

  22. 22.

    Ida M, Satoh A, Matsumoto I, Kojima-Aikawa K (2004) Human annexin V binds to sulfatide: contribution to regulation of blood coagulation. J Biochem 135:583–588

    CAS  Article  Google Scholar 

  23. 23.

    Monceau V, Belikova Y, Kratassiouk G, Charue D, Camors E, Communal C et al (2004) Externalization of endogenous annexin A5 participates in apoptosis of rat cardiomyocytes. Cardiovasc Res 64:496–506

    CAS  Article  Google Scholar 

  24. 24.

    Mirnikjoo B, Balasubramanian K, Schroit AJ (2009) Suicidal membrane repair regulates phosphatidylserine externalization during apoptosis. J Biol Chem 284:22512–22516

    CAS  Article  Google Scholar 

  25. 25.

    Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ et al (1996) Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335:1182–1189

    CAS  Article  Google Scholar 

  26. 26.

    Yussman MG, Toyokawa T, Odley A, Lynch RA, Wu G, Colbert MC et al (2002) Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med 8:725–730

    CAS  Article  Google Scholar 

  27. 27.

    Haider N, Arbustini E, Gupta S, Liu H, Narula N, Hajjar R et al (2009) Concurrent upregulation of endogenous proapoptotic and antiapoptotic factors in failing human hearts. Nat Clin Pract Cardiovasc Med 6:250–261

    CAS  PubMed  Google Scholar 

  28. 28.

    Tahan F, Akar HH, Saraymen B (2015) Exhaled breath condensate annexin A5 levels in exercise-induced bronchoconstriction in asthma: A preliminary study. Allergol Immunopathol (Madr) 43:538–542

    CAS  Article  Google Scholar 

  29. 29.

    Sun B, Bai Y, Zhang L, Gong L, Qi X, Li H et al (2016) Quantitative proteomic profiling the molecular signatures of Annexin A5 in lung squamous carcinoma cells. PLoS ONE 11:e0163622

    Article  Google Scholar 

  30. 30.

    Hashimoto K, Kim H, Oishi H, Chen M, Iskender I, Sakamoto J et al (2016) Annexin V homodimer protects against ischemia reperfusion-induced acute lung injury in lung transplantation. J Thorac Cardiovasc Surg 151:861–869

    CAS  Article  Google Scholar 

  31. 31.

    Buckley S, Shi W, Xu W, Frey MR, Moats R, Pardo A et al (2015) Increased alveolar soluble annexin V promotes lung inflammation and fibrosis. Eur Respir J 46:1417–1429

    CAS  Article  Google Scholar 

  32. 32.

    Schurgers LJ, Burgmaier M, Ueland T, Schutters K, Aakhus S, Hofstra L et al (2016) Circulating annexin A5 predicts mortality in patients with heart failure. J Intern Med 279:89–97

    CAS  Article  Google Scholar 

  33. 33.

    Yamaguchi M, Kokai Y, Imai S, Utsumi K, Matsumoto K, Honda H et al (2010) Investigation of annexin A5 as a biomarker for Alzheimer’s disease using neuronal cell culture and mouse model. J Neurosci Res 88:2682–2692

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number HC15C1335).

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Correspondence to An-Soo Jang.

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The authors declare that they have no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Lee, SH., Lee, PH., Kim, BG. et al. Annexin A5 Protein as a Potential Biomarker for the Diagnosis of Asthma. Lung 196, 681–689 (2018). https://doi.org/10.1007/s00408-018-0159-x

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Keywords

  • Annexin A5
  • Asthma
  • Epithelial cells
  • Fibroblasts
  • Plasma