Retinol-binding protein 4 and plasminogen activator inhibitor-1 as potential prognostic biomarkers of non-allergic asthma caused by obesity in adolescents
Main Article Content
Keywords
non-allergic asthma, obesity, prognostic, biomarker, RBP4, PAI-1
Abstract
Background: Non-allergic asthma caused by obesity is a complication of the low-grade chronic inflammation inherent in obesity. Consequently, the serum concentrations of adipokines such as retinol-binding protein 4 (RBP4) and plasminogen activator inhibitor-1 (PAI-1) increase. No gold standard molecule for the prediction of non-allergic asthma among obese patients has been identified.
Objective: To evaluate RBP4 and PAI-1 as prognostic biomarkers of non-allergic asthma caused by obesity.
Methods: A cross-sectional study between four groups of adolescents: (1) healthy (n = 35), (2) allergic asthma without obesity (n = 28), (3) obesity without asthma (n = 33), and (4) non-allergic asthma with obesity (n = 18).
Results: RBP4 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (39.2 ng/mL [95% confidence interval (CI): 23.8–76.0] vs. 23.5 ng/mL [95% CI: 3.2–33.5], p < 0.01), and PAI-1 was higher in the non-allergic asthma with obesity group than in the obesity without asthma group (21.9 ng/mL [95% CI: 15.7–26.5] vs. 15.9 ng/mL [95% CI: 9.4–18.2], p < 0.05). Receiver operating characteristic (ROC) curve analysis demonstrated that the serum RBP4 cut-off value was >42.78 ng/mL, with an area under the ROC curve (AUC) of 0.741 (95% CI: 0.599–0.853, p = 0.001), considered acceptable. The PAI-1 cut-off value was >12.0 ng/mL, with an AUC of 0.699 (95% CI: 0.554–0.819, p = 0.008), considered fair.
Conclusions: RBP4 may be useful to predict non-allergic asthma among obese adolescents in clinical practice.
References
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32. Cho S, Kang J, Lyttle C, Harris K, Daley B, Grammer L, et al. Association of elevated plasminogen activator inhibitor 1 levels with diminished lung function in patients with asthma. Ann Allergy Asthma Immunol. 2011;106:371–377. 10.1016/j.anai.2010.12.021
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34. Tashiro H, Shore SA. Obesity and severe asthma. Allergol Int. 2019;68:135–142. 10.1016/j.alit.2018.10.004
35. Sze E, Bhalla A, Nair P. Mechanisms and therapeutic strategies for non-T2 asthma. Allergy. 2020;75(2):311–325. 10.1111/all.13985
36. Yuan Y, Ran N, Xiong L, Wang G, Guan X, Wang Z, et al. Obesity-related asthma: immune regulation and potential targeted therapies. J Immunol Res. 2018;2018:1943497. 10.1155/2018/1943497
37. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–2194. 10.1001/jama.2013.281053
38. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002;246:1–190.
39. Polgar G, Promadhat V. Standard values in pulmonary function testing in children: techniques and standards. Philadelphia, PA: Saunders; 1971.
40. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. Standardization of spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200:e70–e88. 10.1164/rccm.201908-1590ST
41. Tanner JM. Growth at adolescence. Oxford, UK: Blackwell; 1962.
42. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–35. 10.1002/1097-0142(1950)3:1<32::aid-cncr2820030106>3.0.co;2-3
2. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention, 2019 revision. [internet] [accessed January 15, 2020]. Available from: http://www.ginasthma.org/
3. World Health Organization. Asthma. [internet] [Accessed January 20, 2020]. Available from: https://www.who.int/news-room/fact-sheets/detail/asthma
4. Kanneganti TD, Dixit VD. Immunological complications of obesity. Nat Immunol. 2012;13:707–712. 10.1038/ni.2343
5. Beuther DA, Sutherland ER. Overweight, obesity and incident asthma: a meta-analysis of prospective epidemiologic studies. Am J Respir Crit Care Med. 2007;175:661–666. 10.1164/rccm.200611-1717OC
6. Deng X, Ma J, Yuan Y, Zhang Z, Niu W. Association between overweight or obesity and the risk for childhood asthma and wheeze: an updated meta-analysis on 18 articles and 73 252 children. Pediatr Obes. 2019;14:e12532. 10.1111/ijpo.12532
7. Castro-Rodriguez JA, Holberg CJ, Morgan WJ, Wright AL, Martinez FD. Increased incidence of asthmalike symptoms in girls who become overweight or obese during the school years. Am J Respir Crit Care Med. 2001;163:1344–1349. 10.1164/ajrccm.163.6.2006140
8. Holguin F, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Erzurum SC, et al. Obesity and asthma: an association modified by age of asthma onset. J Allergy Clin Immunol. 2011;127:1486–1493. 10.1016/j.jaci.2011.03.036
9. Dixon AE, Poynter ME. Mechanisms of asthma in obesity. Pleiotropic aspects of obesity produce distinct asthma phenotypes. Am J Respir Cell Mol Biol. 2016;54:601–608. 10.1165/rcmb.2016-0017PS
10. Peters U, Dixon AE, Forno E. Obesity and asthma. J Allergy Clin Immunol. 2018;141:1169–1179. 10.1016/j.jaci.2018.02.004
11. Boonpiyathad T, Sözener ZC, Satitsuksanoa P, Akdis CA. Immunologic mechanisms in asthma. Semin Immunol. 2019;46:101333. 10.1016/j.smim.2019.101333
12. Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11:738–749. 10.1038/nri3071
13. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112:1796–1808. 10.1172/JCI19246
14. Chehimi M, Vidal H, Eljaafari A. Pathogenic role of IL-17-producing immune cells in obesity, and related inflammatory diseases. J Clin Med. 2017;6.pii: E68. 10.3390/jcm6070068
15. Leiria LO, Martins MA, Saad MJ. Obesity and asthma: beyond Th2 inflammation. Metabolism. 2015;64:172–181. 10.1016/j.metabol.2014.10.002
16. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11(2):85–97. 10.1038/nri2921
17. Quadro L, Blaner WS, Salchow DJ, Vogel S, Piantedosi R, Gouras P, et al. Impaired retinal function and vitamin A availability in mice lacking retinol-binding protein. EMBO J. 1999;18:4633–4644. 10.1093/emboj/18.17.4633
18. Huang F, Del-Río-Navarro BE, Leija-Martinez J, Torres-Alcantara S, Ruiz-Bedolla E, Hernández-Cadena L, et al. Effect of omega-3 fatty acids supplementation combined with lifestyle intervention on adipokines and biomarkers of endothelial dysfunction in obese adolescents with hypertriglyceridemia. J Nutr Biochem. 2019;64:162–169. 10.1016/j.jnutbio.2018.10.012
19. Park YH, Kim KW, Lee KE, Kim ES, Sohn MH, Kim KE. Clinical implications of serum retinol-binding protein 4 in asthmatic children. J Korean Med Sci. 2009;24:1010–1014. 10.3346/jkms.2009.24.6.1010
20. Huang F, Del-Río-Navarro BE, Torres-Alcántara S, Pérez-Ontiveros JA, Ruiz-Bedolla E, Saucedo-Ramírez OJ, et al. Adipokines, asymmetrical dimethylarginine, and pulmonary function in adolescents with asthma and obesity. J Asthma. 2017;54:153–161. 10.1080/02770903.2016.1200611
21. Klöting N, Graham TE, Berndt J, Kralisch S, Kovacs P, Wason CJ, et al. Serum retinol-binding protein is more highly expressed in visceral than in subcutaneous adipose tissue and is a marker of intra-abdominal fat mass. Cell Metab. 2007;6:79–87. 10.1016/j.cmet.2007.06.002
22. Periyalil HA, Wood LG, Wright TA, Karihaloo C, Starkey MR, Miu AS. Obese asthmatics are characterized by altered adipose tissue macrophage activation. Clin Exp Allergy. 2018;48:641–649. 10.1111/cea.13109
23. Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, et al. Enhanced expression of PAI-1 in visceral fat: possible contributor to vascular disease in obesity. Nat Med. 1996;2:800–803. 10.1038/nm0796-800
24. Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, et al. Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes. 2000;49:13741380. 10.2337/diabetes.49.8.1374
25. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med. 2001;344:350–362. 10.1056/NEJM200102013440507
26. Cho SH, Ryu CH, Oh CK. Plasminogen activator inhibitor-1 in the pathogenesis of asthma. Exp Biol Med (Maywood). 2004;229:138–146. 10.1177/153537020422900202
27. Cho SH, Tam SW, Demissie-Sanders S, Filler SA, Oh CK. Production of plasminogen activator inhibitor-1 by human mast cells and its possible role in asthma. J Immunol. 2000;165:3154–3161. 10.4049/jimmunol.165.6.3154
28. Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest. 1996;97:232–237. 10.1172/JCI118396
29. Oh CK, Ariue B, Alban RF, Shaw B, Cho SH. PAI-1 promotes extracellular matrix deposition in the airways of a murine asthma model. Biochem Biophys Res Commun. 2002;294:1155–1160. 10.1016/S0006-291X(02)00577-6
30. Swaisgood CM, Aronica MA, Swaidani S, Plow EF. Plasminogen is an important regulator in the pathogenesis of a murine model of asthma. Am J Respir Crit Care Med. 2007;176:333–342. 10.1164/rccm.200609-1345OC
31. Huang F, del-Río-Navarro BE, Alcántara ST, Ontiveros JA, Cienfuegos DR, Bello González SA, et al. Plasminogen activator inhibitor-1, fibrinogen, and lung function in adolescents with asthma and obesity. Endocr Res. 2012;37:135–144. 10.3109/07435800.2012.654555
32. Cho S, Kang J, Lyttle C, Harris K, Daley B, Grammer L, et al. Association of elevated plasminogen activator inhibitor 1 levels with diminished lung function in patients with asthma. Ann Allergy Asthma Immunol. 2011;106:371–377. 10.1016/j.anai.2010.12.021
33. De Taeye B, Smith LH, Vaughan DE. Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease. Curr Opin Pharmacol. 2005;5:149–154. 10.1016/j.coph.2005.01.007
34. Tashiro H, Shore SA. Obesity and severe asthma. Allergol Int. 2019;68:135–142. 10.1016/j.alit.2018.10.004
35. Sze E, Bhalla A, Nair P. Mechanisms and therapeutic strategies for non-T2 asthma. Allergy. 2020;75(2):311–325. 10.1111/all.13985
36. Yuan Y, Ran N, Xiong L, Wang G, Guan X, Wang Z, et al. Obesity-related asthma: immune regulation and potential targeted therapies. J Immunol Res. 2018;2018:1943497. 10.1155/2018/1943497
37. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191–2194. 10.1001/jama.2013.281053
38. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002;246:1–190.
39. Polgar G, Promadhat V. Standard values in pulmonary function testing in children: techniques and standards. Philadelphia, PA: Saunders; 1971.
40. Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. Standardization of spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019;200:e70–e88. 10.1164/rccm.201908-1590ST
41. Tanner JM. Growth at adolescence. Oxford, UK: Blackwell; 1962.
42. Youden WJ. Index for rating diagnostic tests. Cancer. 1950;3:32–35. 10.1002/1097-0142(1950)3:1<32::aid-cncr2820030106>3.0.co;2-3
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May 1, 2021
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Leija-Martínez, J. J., Patricio-Román, K. L., Del-Río-Navarro, B. E., Villalpando-Carrión, S., Reyes-Garay, J. A., Vélez–Reséndiz, J. M., Romero-Nava, R., Sanchéz-Muñoz, F., Villafaña, S., Muñoz-Hernández, O., Hong, E., Ocharan Hernández, M. E., & Huang, F. (2021). Retinol-binding protein 4 and plasminogen activator inhibitor-1 as potential prognostic biomarkers of non-allergic asthma caused by obesity in adolescents. Allergologia Et Immunopathologia, 49(3), 21-29. https://doi.org/10.15586/aei.v49i3.73
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How to Cite
Leija-Martínez, J. J., Patricio-Román, K. L., Del-Río-Navarro, B. E., Villalpando-Carrión, S., Reyes-Garay, J. A., Vélez–Reséndiz, J. M., Romero-Nava, R., Sanchéz-Muñoz, F., Villafaña, S., Muñoz-Hernández, O., Hong, E., Ocharan Hernández, M. E., & Huang, F. (2021). Retinol-binding protein 4 and plasminogen activator inhibitor-1 as potential prognostic biomarkers of non-allergic asthma caused by obesity in adolescents. Allergologia Et Immunopathologia, 49(3), 21-29. https://doi.org/10.15586/aei.v49i3.73