Аdvanced glycation end-products as novel biomarkers of eosinophil-derived lung inflammatory diseases (literature review)


  • A. Gamian Institute of Immunology and Experimental Therapy Polish Academy of Science, Department of Immunology of Infectious Diseases, Rudolfa Weigla str, 12, Wroclaw, 53-114, Poland https://orcid.org/0000-0002-2206-6591
  • S.O. Zubchenko Danylo Halytsky Lviv National Medical University, Department of Clinical Immunology and Allergology, Pekarska str., 69, Lviv, 79010, Ukraine https://orcid.org/0000-0003-4471-4884
  • A.M. Havrylyuk Danylo Halytsky Lviv National Medical University, Department of Clinical Immunology and Allergology, Pekarska str., 69, Lviv, 79010, Ukraine https://orcid.org/0000-0001-9808-8896
  • I.Y. Kril Danylo Halytsky Lviv National Medical University, Department of Clinical Immunology and Allergology, Pekarska str., 69, Lviv, 79010, Ukraine https://orcid.org/0000-0002-6728-5827
  • V.V. Chopyak Danylo Halytsky Lviv National Medical University, Department of Clinical Immunology and Allergology, Pekarska str., 69, Lviv, 79010, Ukraine https://orcid.org/0000-0003-3127-2028




advanced glycation end-products, allergy, eosinophils-derived inflammation, neutrophil-derived inflammation


Advanced glycation end-products (AGEs) are created during the process of glycation of cells from various tissues and fluids and are a heterogeneous group of molecules formed from the nonenzymatic reaction of reducing sugars with the amino group of proteins, lipids, and nucleic acid. In normal conditions, they play the immunoregulatory role. In pathologic conditions AGEs activate the receptors for advanced glycation end products (RAGE) and cause long-lasting inflammation. RAGE participates actively in various disorders such as rheumatoid arthritis, diabetes, etc. However, there is relatively small number of scientific studies on the possibility of using the role of AGE in the pathogenesis of allergic diseases. RAGE transcript and protein are expressed in the lung by pulmonary type I alveolar epithelial cells, suggesting that RAGE has an important role in lung pathophysiology. They repress some endogenous autoregulatory functions leading to many diseases, including allergy.  Oxidative stress increases the inflammatory reaction in asthma and allergies. Long-lasting inflammation followed by free radicals production are important factors involved in allergic reactions, they negatively influence the incidence and prognosis of allergy. RAGEs are expressed on circulating immune cells, they activate NF kappaB and intracellular oxidative stress also increases the inflammatory reaction in asthma and allergies. The membrane RAGE (mRAGE) signaling is proinflammatory, whereas soluble RAGE (sRAGE), a secreted form of RAGE, is generally anti-inflammatory. The study of AGEs, soluble RAGE, ligands of RAGE HMGB1, and S100A8/A913 and IL-33 is useful in the context of their considering as biomarkers to the differentiation diagnostic between eosinophils-derived and neutrophil-derived asthma/AAD. The mean serum levels of RAGE may be the target of new therapeutic interventions.


Akirav EM, Henegariu O, Preston-Hurlburt P, Schmidt AM, Clynes R, Herold KC. The receptor for ad­vanced glycation end products (RAGE) affects T cell differentiation in OVA induced asthma. PLoS One. 2014;9:e95678. eCollection 2014. doi: https://doi.org/10.1371/journal.pone.0095678

Al-Robaiy S, Weber B, Simm A, Diez C, Rolews­ka P, Silber RE, et al. The receptor for advanced glycation end-products supports lung tissue biomechanics, Am. J. Physiol.Lung Cell Mol. Physiol.2013;305:L491-L500. Epub 2013 Aug 30. doi: https://doi.org/10.1152/ajplung.00090.2013

Perrone A., Giovino A., Benny J., Martinelli F. Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects. Hindawi. Oxidative Medicine and Cellular Longevity. 2020;2020:18. ArticleID 3818196. doi: https://doi.org/10.1155/2020/3818196

Bediwy AS, Hassan SM, El-Najjar MR. Receptor of advanced glycation end products in childhood asthma exacerbation. Egyptian Journal of Chest Diseases and Tuberculosis. 2016;65:15-18. doi: https://doi.org/10.1016/j.ejcdt.2015.10.008

Boitano S, Safdar Z, Welsh DG, Bhattacharya J, Koval M. Cell-cell interactions in regulating lung function. Am J Physiol Lung Cell Mol Physiol. 2004;287:L455-9. doi: https://doi.org/10.1152/ajplung.00172.2004

Brisslert M, Amu S, Pullerits R. Intra-peritoneal RAGE treatment induces alterations in the cellular distri­bu­tion of CD19(þ), CD3(þ) and Mac-1(þ) cells in lymphoid or­gans and peritoneal cavity, Cell Tissue Res. 2013;351:139-48.

doi: https://doi.org/10.1007/s00441-012-1508-3

Chen Y, Akirav EM, Chen W, Henegariu O, Mo­ser B, Desai D, et al. RAGE ligation affects Tcell activation and controls Tcell differentiation, J.Immunol (Baltimore, MD). 2008;181:4272-8. doi: https://doi.org/10.4049/jimmunol.181.6.4272

Demling N, Ehrhardt C, Kasper M, et al. Promo­tion of cell adherence and spreading: a novel function of RAGE, the highly selective differentiation marker of human alveolar epithelial type I cells. Cell Tiss Res. 2006;323:475-88.

doi: https://doi.org/10.1007/s00441-005-0069-0

El-Seify MY, Fouda EM, Nabih ES. Serum level of soluble receptor for advanced glycation end products in asthmatic children and its correlation to severity and pulmonary functions, Clin. Lab. 2014;60(6):957-62. doi: https://doi.org/10.7754/Clin.Lab.2013.130418

Fehrenbach H, Kasper M, Tschernig T, Shearman MS, Schuh D, Muller M. Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localization in rat and human lung. Cell Mol Biol (Noisy-le-grand). 1998;44:1147-57. Available from: https://www.ncbi.nlm.nih.gov/pubmed/9846897

Gao J, Iwamoto H, Koskela J, Alenius H, Hattori N, Kohno N, et al. Characterization of sputum biomarkers for asthma–COPD overlap syndrome International Journal of COPD. 2016;11:2457-65. doi: https://doi.org/10.2147/COPD.S113484

Golab J, Jakobisiak M, Lasek W, Stoklosa T. Im­munologia (nowe wydanie). Warszawa: Wydawnictwo naukowe PWN SA; 2017;498.

Han K. Suzukawa M. Yamaguchi M. Sugimoto N. Nakase Y. Toda T, et al. The in vitro Effects of Ad­vanced Glycation End Products on Basophil Functions. International Archives of Allergy and Immunology. 2016;40:345-51. Epub 2011 Jun 1. doi: https://doi.org/10.1159/000327298

Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, et al. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet. 2010;42:45-52. Epub 2009 Dec 13. doi: https://doi.org/10.1038/ng.500

Hara K, Iijima K, Elias MK, Seno S, Tojima I, Ko­bayashi T, et al. Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in the respiratory mucosa. J Immunol. 2015;192:4032-42. doi: https://doi.org/10.4049/jimmunol.1400110

Iwamoto H, Gao J, Koskela J., Kinnula V, Ko­bayashi H, Laitinen T, et al. Differences in plasma and sputum biomarkers between COPD and COPD-asthma overlap, Eur. Respir. J. 2014;43:421-9. doi: https://doi.org/10.1183/09031936.00024313

Kailash Prasad, Manish Mishra. AGE-RAGE Stress, Stressors, and Antistressors in Health and Disease. Int J Angiol. 2018 Mar;27(1):1-12. doi: https://doi.org/10.1055/s-0037-1613678

KleinWolterink RG, Kleinjan A, van Nim­wegen M, Bergen I, de Bruijn M, Levani Y, et al. Pul­monary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol. 2012;42:1106-16. doi: https://doi.org/10.1002/eji.201142018

Kuzan A, Chwiłkowska A, Maksymowicz K, Bronowicka-Szydełk A, Stach K., Pezowicz C, et al. Ad­vanced glycation end products as a source of artifacts in immunoenzymatic methods. Glycoconj J. 2018;35:95-103. doi: https://doi.org/10.1007/s10719-017-9805-4

Liska J, Holecek V, Siala K, Sobotová S, Trefil L, Racek J, et al. Umbilical IgE and Advanced Glycation Products in Association with Allergies in Childhood. Immun., Endoc. & Metab. Agents in Med. Chem. 2016;16:1-5. doi: https://doi.org/10.2174/1871522216666161018145434

Lorenzo GD, Minciullo PL, Leto-Barone MS, La Piana S, La Porta G, Saija A, et al. Differences in the Behavior of Advanced Glycation End Products and Ad­vanced Oxidation Protein Products in Patients With Allergic Rhinitis. J Investig Allergol Clin Immunol. 2013;23(2):101-106. Available from: https://www.ncbi.nlm.nih.gov/pubmed/23654076

Milutinovic PS, Alcorn JF, Englert JM, Crum LT, Oury TD. The Receptor for Advanced Glycation End Products Is a Central Mediator of Asthma Pathogenesis. The American Journal of Pathology. 2012;181(4):1215-25. doi: https://doi.org/10.1016/j.ajpath.2012.06.031

Miniati M, Monti S, Basta G, et al. Soluble re­ceptor for advanced glycation end products in COPD: relationship with emphysema and chronic cor pulmonale: a case-control study. Respir Res. 2011;12:37. doi: https://doi.org/10.1186/1465-9921-12-37

Oczypok EA, Milutinovic PS, Alcorn JF, Kha­re A, Crum LT, Manni ML, et al. Pulmonary receptor for advanced glycation end-products promotes asthma patho­genesis through IL-33 and accumulation of group 2 in­nate lymphoid cells. J Allergy Clin Immunol. 2015;136:747-56. doi: https://doi.org/10.1016/j.jaci.2015.03.011

Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A. Role of advanced glycation end pro­ducts in cellular signaling. Redox Biology. 2014;2:411-29. doi: https://doi.org/10.1016/j.redox.2013.12.016

Pietkiewicz J, Seweryn E, Bartyś A, Gamian A. Receptors for advanced glycation end products and their physiological and clinical significance. Postepy Hig Med Dosw. 2008;62:511-523. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18936727

Prasad K, Tiwari S. Therapeutic Interventions for Advanced Glycation-End Products and its Receptor. Mediated Cardiovascular Disease. 2017;23(6):937-43. doi: https://doi.org/10.2174/1381612822666161006143032

Repapi E, Sayers I, Wain LV, Burton PR, John­son T, Obeidat M, et al. Genom-wide association study identifies five loci associated with lung function. Nat Genet. 2010;42:36-44. doi: https://doi.org/10.1038/ng.501

Sirois CM, Jin T, Miller AL, Bertheloot D, Naka­mura H, Horvath GL, et al. RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J. Exp. Med. 2013;210:2447-63. doi: https://doi.org/10.1084/jem.20120201

Smith PK, Masilamani M, Li XM, Sampson HA. The false alarm hypothesis: Food allergy is associated with high dietary advanced glycation end-products and proglycating dietary sugars that mimic alarmins. J Allergy Clin Immunol. 2017;139(2):429-37. doi: https://doi.org/10.1016/j.jaci.2016.05.040

Staniszewska M, Jarosz S, Jon M, Gamian A. Advanced glycation end-products prepared in solution under high pressure contain epitopes distinct from those formed in the dry reaction at high temperature. Arch Immunol Ther Exp. 2005;53:71-78. Available from: https://www.ncbi.nlm.nih.gov/pubmed/15761378

Sukkar MB, Wood LG, Tooze M, et al. Soluble RAGE is deficient in neutrophilic asthma and COPD. Eur Respir J. 2012;39:721-9. doi: https://doi.org/10.1183/09031936.00022011

Suzukawa M, Yamaguchi M, Han K, Toda T, Na­gase H, Ohta K. The Role of Advanced Glycation Endpro­ducts (AGEs) on Basophil Functions. 2015;35(3):212-17. doi: https://doi.org/10.1016/j.jaci.2010.12.832

Vesnina LE, Izmailova OV, Shlykova OA, Kai­dashev IP. [Features of NF-κB-mediated signal transduc­tion and development of systemic inflammation in pa­tients with diseases of internal organs are determined by microbial factor and individual reactivity of the body (review of own research findings)]. Problemy ekolohii ta medytsyny. 2015;19(3-4):23-30. Ukrainian. Available from: https://ecomed-journal.org/index.php/journal/article/view/49

Ullah MA, Loh Z, Gan WJ, Zhang V, Yang H, Li JH, et al. Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation. J Allergy Clin Immunol. 2014;134: 440-50. doi: https://doi.org/10.1016/j.jaci.2013.12.1035

Zubchenko SA, Kril IY, Chopyak VV. [Patho­genesis of allergic inflammation with the participation of IL-17 and IL-23 cytokines in patients with chronic Epstein-Barr virus persistence in active and latent phases]. Asthma end Allergy. 2019;4:31-36. Ukrainian. doi: https://doi.org/10.31655/2307-3373-2019-4-31-36

Zuo L, Lucas K, Fortuna ChA, Chuang Ch-Ch, Best T. Molecular Regulation of Toll-like Receptors in Asthma and COPD. Frontiers in Physiology. 2015 Nov;6:10. doi: https://doi.org/10.3389/fphys.2015.00312

Pertseva TA, Hashynova EYu. [Difficult Asthma: Life Goes On]. Zdorove Ukrainy. 2007;4:35-36. Ukrainian




How to Cite

Gamian A, Zubchenko S, Havrylyuk A, Kril I, Chopyak V. Аdvanced glycation end-products as novel biomarkers of eosinophil-derived lung inflammatory diseases (literature review). Med. perspekt. [Internet]. 2020Dec.28 [cited 2022May16];25(4):99-106. Available from: http://journals.uran.ua/index.php/2307-0404/article/view/221245