Soluble receptor for advanced glycation end products and soluble interleukin-4 receptor in plasma and exhaled breath condensate as potential markers of asthma severity in children

Introduction. Asthma in children is characterized by chronic inflammation of the lower airways. The verification of reliable pro-inflammatory biomarkers, particularly non-invasive ones, is crucial for the diagnosis and treat[1]ment of childhood asthma. Aim. To evaluate the levels of soluble receptors for advanced glycation end products (sRAGE) and soluble interleukin-4 receptor (sIL-4R) in blood plasma and exhaled breath condensate (EBC) as potential biomarkers of bronchial asthma severity in children. Materials and methods. The study enrolled 195 children aged 6-17 years: 104 children with asthma and 91 children without any history of atopic diseases at baseline or during examination. The diagnosis and severity assessment of asthma were determined according to the Global Initiative for Asthma guidelines (GINA, 2021). EBC samples were collected using RTube devices (Respiratory Research, USA). The levels of sRAGE and sIL-4R were measured using magnetic bead-based multiplex immunoassay (MAGPIX, Luminex, USA). Results. Among 169 analyzed EBC samples, sRAGE was not detected in any sample above the minimum detectable level (14 pg/mL). In contrast, sIL- 4R levels exceeding the minimum detectable level (3 pg/mL) were found in 166 samples (98%). Plasma sRAGE levels were significantly lower in children with asthma (197.7 pg/mL) compared to controls (229.0 pg/mL; p=0.017). Similarly, EBC sIL-4R concentrations were significantly lower in children with asthma (120.3 pg/mL) compared to the control group (165.4 pg/mL; p<0.001). A statistically significant correlation was observed between plasma sRAGE levels and asthma severity (p=0.013, Kruskal-Wallis test). Conclusion. The measurement of plasma sRAGE and EBC sIL-4R levels appears to be a promising approach in developing novel biomarkers for the diagnosis, severity assessment, and monitoring of bronchial asthma in children.

1. Lambrecht B.N., Hammad H., Fahy J.V. The cytokines of asthma // Immunity. 2019. Vol.50, Iss.4. P.975–991. https://doi.org10.1016/j.immuni.2019.03.018

2. Ul-Haq Z., Naz S., Mesaik M.A. Interleukin-4 receptor signaling and its binding mechanism: a therapeutic insight from inhibitors tool box // Cytokine Growth Factor Rev. 2016. Vol.32. P.3–15. https://doi.org10.1016/j.cytogfr.2016.04.002

3. Delrue C., Speeckaert R., Delanghe J.R., Speeckaert M.M. Breath of fresh air: investigating the link between AGEs, sRAGE, and lung diseases // Vitam. Horm. 2024. Vol.125. P.311–365. https://doi.org10.1016/bs.vh.2024.01.003

4. Pratte K.A., Curtis J.L., Kechris K., Couper D., Cho M.H., Silverman E.K., Demeo D.L., Sciurba F.C., Zhang Y., Ortega V.E., O'neal W.K., Gillenwater L.A., Lynch D.A., Hoffman E.A., Newell J.D., Jr., Comellas A.P., Castaldi P.J., Miller B.E., Pouwels S.D., Hacken N., Bischoff R., Klont F., Woodruff P.G., Paine R., Barr R.G., Hoidal J., Doerschuk C.M., Charbonnier J.P., Sung R., Locantore N., Yonchuk J.G., Jacobson S., Tal-Singer R., Merrill D., Bowler R.P. Soluble receptor for advanced glycation end products (sRAGE) as a biomarker of COPD // Respir. Res. 2021. Vol.22, Iss.1. Article number:127. https://doi.org10.1186/s12931-021-01686-z

5. Raita Y., Zhu Z., Freishtat R.J., Fujiogi M., Liang L., Patregnani J.T., Camargo C.A., Hasegawa K. Soluble receptor for advanced glycation end products (sRAGE) and asthma: mendelian randomisation study // Pediatr. Allergy Immunol. 2021. Vol.32, Iss.5. P.1100–1103. https://doi.org10.1111/pai.13478

6. Sukkar M.B., Ullah M.A., Gan W.J., Wark P.A., Chung K.F., Hughes J.M., Armour C.L., Phipps S. RAGE: a new frontier in chronic airways disease // Br. J. Pharmacol. 2012. Vol.167, Iss.6. P.1161–1176. https://doi.org10.1111/j.1476-5381.2012.01984.x

7. Davis M.D., Montpetit A.J. Exhaled breath condensate: an update // Immunol. Allergy Clin. North Am. 2018. Vol.38, Iss.4. P.667–678. https://doi.org10.1016/j.iac.2018.06.002

8. Reddel H.K., Bacharier L.B., Bateman E.D., Brightling C.E., Brusselle G.G., Buhl R., Cruz A.A., Duijts L., Drazen J.M., Fitzgerald J.M., Fleming L.J., Inoue H., Ko F.W., Krishnan J.A., Levy M.L., Lin J., Mortimer K., Pitrez P.M., Sheikh A., Yorgancioglu A.A., Boulet L.P. Global Initiative for Asthma Strategy 2021: executive summary and rationale for key changes // Am. J. Respir. Crit. Care Med. 2022. Vol.205, Iss.1. P.17–35. https://doi.org10.1164/rccm.202109-2205PP

9. Zhang F., Su X., Huang G., Xin X.-F., Cao E.H., Shi Y., Song Y. sRAGE alleviates neutrophilic asthma by blocking HMGB1/RAGE signalling in airway dendritic cells // Sci. Rep. 2017. Vol.7, Iss.1. Article number:14268. https://doi.org10.1038/s41598-017-14667-4

10. Sukkar M.B., Wood L.G., Tooze M., Simpson J.L., Mcdonald V.M., Gibson P.G., Wark P.A. Soluble RAGE is deficient in neutrophilic asthma and COPD // Eur. Respir. J. 2012. Vol.39, Iss.3. P.721–729. https://doi.org10.1183/09031936.00022011

11. Li Y., Wu R., Tian Y., Bao T., Tian Z. Fraction of exhaled nitric oxide and soluble receptors for advanced glycation end products are negatively correlated in children with recurrent wheezing // Asian Pac. J. Allergy Immunol. 2017. Vol.35, Iss.1. P.33–37. https://doi.org10.12932/ap0746

12. Alzayadneh E.M., Al Bdour S.A., Elayeh E.R., Ababneh M.M., Al-Ani R.A., Shatanawi A., Al-Iede M., Al-Zayadneh E. Assessment of fraction of exhaled nitric oxide and soluble receptor for advanced glycation end products biomarkers for jordanian asthmatic children // J. Asthma Allergy. 2023. Vol.16. P.793–811. https://doi.org10.2147/jaa.s415481

13. Hu H., Hu X., Wang Z., Gao L., Jin J., Xia J., Huang L., Li S. Clinical value of serum soluble receptor for advanced glycation end products in evaluating the condition of patients with bronchial asthma // Allergy Asthma Proc. 2023. Vol.44, Iss.4. P.258–264. https://doi.org10.2500/aap.2023.44.230027

14. Perkins T.N., Donnell M.L., Oury T.D. The axis of the receptor for advanced glycation endproducts in asthma and allergic airway disease // Allergy. 2021. Vol.76, Iss.5. P.1350–1366. https://doi.org10.1111/all.14600

15. Bui H., Keshawarz A., Hwang S.J., Yao C., Lee G.Y., Recto K., O'connor G.T., Levy D. A genomic approach identifies sRAGE as a putatively causal protein for asthma // J. Allergy Clin. Immunol. 2022. Vol.149, Iss.6. P.1992–1997. https://doi.org10.1016/j.jaci.2021.11.027

16. Renz H., Enssle K., Lauffer L., Kurrle R., Gelfand E.W. Inhibition of allergen-induced IgE and IgG1 production by soluble IL-4 receptor // Int. Arch. Allergy Immunol. 1995. Vol.106, Iss.1. P.46–54. https://doi.org10.1159/000236889

17. Renz H., Bradley K., Enssle K., Loader J.E., Larsen G.L., Gelfand E.W. Prevention of the development of immediate hypersensitivity and airway hyperresponsiveness following in vivo treatment with soluble IL-4 receptor // Int. Arch. Allergy Immunol. 1996. Vol.109, Iss.2. P.167–176. https://doi.org10.1159/000237216

18. Henderson W.R., Emil Y., Maliszewski C.R. Soluble IL-4 receptor inhibits airway inflammation following allergen challenge in a mouse model of asthma // J. Immunol. 2000. Vol.164, Iss.2. P.1086–1095. https://doi.org10.4049/jimmunol.164.2.1086

19. Hackstein H., Hecker M., Kruse S., Bohnert A., Ober C., Deichmann K.A., Bein G. A novel polymorphism in the 5′ promoter region of the human interleukin-4 receptor α-chain gene is associated with decreased soluble interleukin-4 receptor protein levels // Immunogenetics. 2001. Vol.53, Iss.4. P.264–269. https://doi.org10.1007/s002510100324

20. Schauer U., Schmitt M., Müller S., Enssle K., Kurrle R., Sundermann U., Bender A., Wahn U., Rieger C.H. Soluble interleukin-4 receptor in atopic children // Int. Arch. Allergy Immunol. 1995. Vol.108, Iss.2. P.175–182. https://doi.org10.1159/000237136

21. Fitch P.S., Brown V., Schock B.C., Ennis M., Shields M.D. Interleukin-4 and interleukin-4 soluble receptor alpha levels in bronchoalveolar lavage from children with asthma // Ann. Allergy Asthma Immunol. 2003. Vol.90, Iss.4. P.429– 433. https://doi.org10.1016/s1081-1206(10)61828-5