Th17/Treg Ratio in COPD Patients with Normal and High Pulmonary Arterial Hypertension
-
Nima Jadidian
,
Ali Hazrati
,
Arsalan yazdchi
,
Hamed Valizadeh
,
Mohammad Reza Taban-Sadeghi
,
Majid Ahmadi
,
Haleh Mikaeili
Abstract
The airflow limitation is one of the characteristics of chronic obstructive pulmonary disease (COPD), which is not entirely reversible. It seems that factors such as inflammation, hypoxia, and remodeling of pulmonary vessels can increase pulmonary hypertension (PH). This increase in pulmonary arterial hypertension leads to aggravation of disease complications.
Considering the role of immune cells in causing pathological inflammation in the pathogenesis of COPD, it seems that Th17/Treg axis imbalance can be one of the main reasons for the difference in life expectancy in patients with COPD with and without PH.
By measuring and comparing some inflammatory biomarkers in patients with COPD with and without PH, this study tries to introduce these biomarkers to predict the occurrence or nonoccurrence of this complication. This study aims to compare the ratio and activity of Th17 to Treg in patients with COPD with high (20 patients) and normal (20 patients) pulmonary arterial pressure. Five milliliters of blood containing anticoagulant were obtained to isolate peripheral blood mononuclear cells (PBMCs). Then, the ratio of Th17 to Treg, their number, and their activity were evaluated by ELISA, real-time polymerase chain reaction (PCR), and flow cytometry.
Our results show that the amount of inflammatory factors and the population of Th17 cells in patients with COPD with PH is associated with a significant increase in PH compared to patients with COPD without PH, which leads to damage caused by pathological inflammation to the lung tissue and a decrease in the overall survival of the patients.
1. Agustí A, Melen E, DeMeo DL, Breyer-Kohansal R, Faner R. Pathogenesis of chronic obstructive pulmonary disease: understanding the contributions of gene–environment interactions across the lifespan. Lancet Respir Med. 2022;10(5):512-24.
2. Gutiérrez Villegas C, Paz-Zulueta M, Herrero-Montes M, Parás-Bravo P, Madrazo Pérez M. Cost analysis of chronic obstructive pulmonary disease (COPD): a systematic review. Health Econ Rev. 2021;11:1-12.
3. Hogea SP, Tudorache E, Fildan AP, Fira‐Mladinescu O, Marc M, Oancea C. Risk factors of chronic obstructive pulmonary disease exacerbations. Clin Respir J. 2020;14(3):183-97.
4. Rodrigues SdO, Cunha CMCd, Soares GMV, Silva PL, Silva AR, Goncalves-de-Albuquerque CF. Mechanisms, pathophysiology and currently proposed treatments of chronic obstructive pulmonary disease. Pharmaceuticals. 2021;14(10):979.
5. Mocumbi A, Humbert M, Saxena A, Jing Z-C, Sliwa K, Thienemann F, et al. Pulmonary hypertension. Nat Rev Dis Primers. 2024;10(1):1.
6. Southgate L, Machado RD, Gräf S, Morrell NW. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol. 2020;17(2):85-95.
7. Thomas CA, Anderson RJ, Condon DF, de Jesus Perez VA. Diagnosis and management of pulmonary hypertension in the modern era: insights from the 6th world symposium. Pulm Ther. 2020;6:9-22.
8. Tanyeri S, Akbal OY, Keskin B, Hakgor A, Karagoz A, Tokgoz HC, et al. Impact of the updated hemodynamic definitions on diagnosis rates of pulmonary hypertension. Pulm Circ. 2020;10(3):2045894020931299.
9. Park H, Lee HJ, Lee J-K, Park TY, Jin KN, Heo EY, et al. Diffusing capacity as an independent predictor of acute exacerbations in chronic obstructive pulmonary disease. Sci Rep. 2024;14(1):2936.
10. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;32(5):1371-85.
11. Silver JS, Kearley J, Copenhaver AM, Sanden C, Mori M, Yu L, et al. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat Immunol. 2016;17(6):626-35.
12. Laurent S, Boutouyrie P. The structural factor of hypertension: large and small artery alterations. Circ Res. 2015;116(6):1007-21.
13. Van Eeden SF, Sin DD. Chronic obstructive pulmonary disease: a chronic systemic inflammatory disease. Respiration. 2008;75(2):224-38.
14. Gredic M, Blanco I, Kovacs G, Helyes Z, Ferdinandy P, Olschewski H, et al. Pulmonary hypertension in chronic obstructive pulmonary disease. Br J Pharmacol. 2021;178(1):132-51.
15. Huijsmans RJ, de Haan A, ten Hacken NN, Straver RV, van’t Hul AJ. The clinical utility of the GOLD classification of COPD disease severity in pulmonary rehabilitation. Resp Med. 2008;102(1):162-71.
16. Elwing J, Panos RJ. Pulmonary hypertension associated with COPD. Int J Chron Obstruct Pulmon Dis. 2008;3(1):55-70.
17. Aguirre-Franco C, Torres-Duque C, Salazar G, Casas A, Jaramillo C, Gonzalez-Garcia M. Prevalence of pulmonary hypertension in COPD patients living at high altitude. Pulmonology. 2024;30(3):247-53.
18. Choudhury P, Dasgupta S, Kar A, Sarkar S, Chakraborty P, Bhattacharyya P, et al. Bioinformatics analysis of hypoxia associated genes and inflammatory cytokine profiling in COPD-PH. Resp Med. 2024;227:107658.
19. Bouroubi O, Khelifi S, Belkadi L, Zaabat N. Inflammatory profile of COPD reached by hypertension. Europ Resp Society; 2024.
20. Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018;18(12):773-89.
21. Hazrati A, Mirarefin SMJ, Malekpour K, Rahimi A, Khosrojerdi A, Rasouli A, et al. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells. Front Immunol. 2024;15:1469696.
22. Hazrati A, Malekpour K, Soudi S, Hashemi SM. Mesenchymal stromal/stem cells and their extracellular vesicles application in acute and chronic inflammatory liver diseases: emphasizing on the anti-fibrotic and immunomodulatory mechanisms. Front Immunol. 2022;13:865888.
23. Kraik K, Tota M, Laska J, Łacwik J, Paździerz Ł, Sędek Ł, et al. The role of transforming growth Factor-β (TGF-β) in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Cells. 2024;13(15):1271.
24. Miyara M, Ito Y, Sakaguchi S. TREG-cell therapies for autoimmune rheumatic diseases. Nat Rev Rheumatol. 2014;10(9):543-51.
25. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3(3):253-7.
26. Lin X, Chen M, Liu Y, Guo Z, He X, Brand D, et al. Advances in distinguishing natural from induced Foxp3+ regulatory T cells. International journal of clinical and experimental pathology. 2013;6(2):116.
27. Ramsdell F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity. 2003;19(2):165-8.
28. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490-500.
29. Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10(11):1178-84.
30. Lange P, Ahmed E, Lahmar ZM, Martinez FJ, Bourdin A. Natural history and mechanisms of COPD. Respirology. 2021;26(4):298-321.
31. Jones S. COPD-Pathology, Diagnosis, Treatment, and Future Directions: Pathology, Diagnosis, Treatment, and Future Directions: BoD–Books on Demand; 2024.
32. Ryu MH, Murphy S, Hinkley M, Carlsten C. COPD exposed to air pollution: a path to understand and protect a susceptible population. Chest. 2024;165(4):836-46.
33. Holtzman MJ, Byers DE, Alexander-Brett J, Wang X. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol. 2014;14(10):686-98.
34. Bhat TA, Panzica L, Kalathil SG, Thanavala Y. Immune dysfunction in patients with chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2015;12(Supplement 2):S169-S75.
35. Butler A, Walton GM, Sapey E. Neutrophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease. COPD. 2018;15(4):392-404.
36. Ponce-Gallegos MA, Ramírez-Venegas A, Falfán-Valencia R. Th17 profile in COPD exacerbations. Int J Chron Obstruct Pulmon Dis. 2017:1857-65.
37. Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev. 2008;223(1):87-113.
38. Vargas-Rojas MI, Ramírez-Venegas A, Limón-Camacho L, Ochoa L, Hernández-Zenteno R, Sansores RH. Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease. Resp Med. 2011;105(11):1648-54.
39. Nathan SD, Lacasse V, Bell H, Sista P, Di Marino M, Bull T, et al. COPD associated pulmonary hypertension: A post hoc analysis of the PERFECT study. Pulmonary Circul. 2024;14(4):e12430.
40. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Res Crit Care Med. 1995;151(5):1628-31.
41. Joppa P, Petrasova D, Stancak B, Tkacova R. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest. 2006;130(2):326-33.
42. Gupta R. Study of Mineral Bone Disease and Cardiovascular Morbidity in Relation with Fibroblast Growth Factor 23 in Chronic Kidney Disease Patient Presenting to Sree Mookambika Institute of Medical Sciences: Sree Mookambika Institute of Medical Sciences, Kulasekharam; 2019.
43. Yang X, Huo B, Zhong X, Su W, Liu W, Li Y, et al. Imbalance between subpopulations of regulatory T cells in patients with acute exacerbation of COPD. COPD. 2017;14(6):618-25.
44. Hou J, Sun Y, Hao Y, Zhuo J, Liu X, Bai P, et al. Imbalance between subpopulations of regulatory T cells in COPD. Thorax. 2013;68(12):1131-9.
45. Qu X, Yi X, Zhong H, Ruan W, Huang D. Effect and mechanism of imbalance via Th9 cells and Th17/Treg cells in inflammatory and fibrotic phases of pulmonary fibrosis in mice. Biotechnology and Genetic Engineering Reviews. 2024;40(3):3007-17.
46. Li X-N, Pan X, Qiu D. Imbalances of Th17 and Treg cells and their respective cytokines in COPD patients by disease stage. International Journal of Clinical and Experimental Medicine. 2014;7(12):5324.
47. Zhu R, Xie X, Wang N, Chen L, Hong Y. The T helper type 17/regulatory T cell imbalance was associated with Ras‐GTP ase overexpression in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease. Immunology. 2019;157(4):304-11.
48. Baroja ML, Lorre K, Van Vaeck F, Ceuppens JL. The anti-T cell monoclonal antibody 9.3 (anti-CD28) provides a helper signal and bypasses the need for accessory cells in T cell activation with immobilized anti-CD3 and mitogens. Cell Immunol. 1989;120(1):205-17.
49. Hautefort A, Girerd B, Montani D, Cohen-Kaminsky S, Price L, Lambrecht BN, et al. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest. 2015;147(6):1610-20.
50. Turner JA, Stephen-Victor E, Wang S, Rivas MN, Abdel-Gadir A, Harb H, et al. Regulatory T cell-derived TGF-β1 controls multiple checkpoints governing allergy and autoimmunity. Immunity. 2020;53(6):1202-14. e6.
51. Hall JA, Pokrovskii M, Kroehling L, Kim B-R, Kim SY, Wu L, et al. Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. Immunity. 2022;55(11):2027-43. e9.
52. Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, et al. Foxp3 transcription-factor-dependent and-independent regulation of the regulatory T cell transcriptional signature. Immunity. 2007;27(5):786-800.
2. Gutiérrez Villegas C, Paz-Zulueta M, Herrero-Montes M, Parás-Bravo P, Madrazo Pérez M. Cost analysis of chronic obstructive pulmonary disease (COPD): a systematic review. Health Econ Rev. 2021;11:1-12.
3. Hogea SP, Tudorache E, Fildan AP, Fira‐Mladinescu O, Marc M, Oancea C. Risk factors of chronic obstructive pulmonary disease exacerbations. Clin Respir J. 2020;14(3):183-97.
4. Rodrigues SdO, Cunha CMCd, Soares GMV, Silva PL, Silva AR, Goncalves-de-Albuquerque CF. Mechanisms, pathophysiology and currently proposed treatments of chronic obstructive pulmonary disease. Pharmaceuticals. 2021;14(10):979.
5. Mocumbi A, Humbert M, Saxena A, Jing Z-C, Sliwa K, Thienemann F, et al. Pulmonary hypertension. Nat Rev Dis Primers. 2024;10(1):1.
6. Southgate L, Machado RD, Gräf S, Morrell NW. Molecular genetic framework underlying pulmonary arterial hypertension. Nat Rev Cardiol. 2020;17(2):85-95.
7. Thomas CA, Anderson RJ, Condon DF, de Jesus Perez VA. Diagnosis and management of pulmonary hypertension in the modern era: insights from the 6th world symposium. Pulm Ther. 2020;6:9-22.
8. Tanyeri S, Akbal OY, Keskin B, Hakgor A, Karagoz A, Tokgoz HC, et al. Impact of the updated hemodynamic definitions on diagnosis rates of pulmonary hypertension. Pulm Circ. 2020;10(3):2045894020931299.
9. Park H, Lee HJ, Lee J-K, Park TY, Jin KN, Heo EY, et al. Diffusing capacity as an independent predictor of acute exacerbations in chronic obstructive pulmonary disease. Sci Rep. 2024;14(1):2936.
10. Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur Respir J. 2008;32(5):1371-85.
11. Silver JS, Kearley J, Copenhaver AM, Sanden C, Mori M, Yu L, et al. Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs. Nat Immunol. 2016;17(6):626-35.
12. Laurent S, Boutouyrie P. The structural factor of hypertension: large and small artery alterations. Circ Res. 2015;116(6):1007-21.
13. Van Eeden SF, Sin DD. Chronic obstructive pulmonary disease: a chronic systemic inflammatory disease. Respiration. 2008;75(2):224-38.
14. Gredic M, Blanco I, Kovacs G, Helyes Z, Ferdinandy P, Olschewski H, et al. Pulmonary hypertension in chronic obstructive pulmonary disease. Br J Pharmacol. 2021;178(1):132-51.
15. Huijsmans RJ, de Haan A, ten Hacken NN, Straver RV, van’t Hul AJ. The clinical utility of the GOLD classification of COPD disease severity in pulmonary rehabilitation. Resp Med. 2008;102(1):162-71.
16. Elwing J, Panos RJ. Pulmonary hypertension associated with COPD. Int J Chron Obstruct Pulmon Dis. 2008;3(1):55-70.
17. Aguirre-Franco C, Torres-Duque C, Salazar G, Casas A, Jaramillo C, Gonzalez-Garcia M. Prevalence of pulmonary hypertension in COPD patients living at high altitude. Pulmonology. 2024;30(3):247-53.
18. Choudhury P, Dasgupta S, Kar A, Sarkar S, Chakraborty P, Bhattacharyya P, et al. Bioinformatics analysis of hypoxia associated genes and inflammatory cytokine profiling in COPD-PH. Resp Med. 2024;227:107658.
19. Bouroubi O, Khelifi S, Belkadi L, Zaabat N. Inflammatory profile of COPD reached by hypertension. Europ Resp Society; 2024.
20. Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018;18(12):773-89.
21. Hazrati A, Mirarefin SMJ, Malekpour K, Rahimi A, Khosrojerdi A, Rasouli A, et al. Mesenchymal stem cell application in pulmonary disease treatment with emphasis on their interaction with lung-resident immune cells. Front Immunol. 2024;15:1469696.
22. Hazrati A, Malekpour K, Soudi S, Hashemi SM. Mesenchymal stromal/stem cells and their extracellular vesicles application in acute and chronic inflammatory liver diseases: emphasizing on the anti-fibrotic and immunomodulatory mechanisms. Front Immunol. 2022;13:865888.
23. Kraik K, Tota M, Laska J, Łacwik J, Paździerz Ł, Sędek Ł, et al. The role of transforming growth Factor-β (TGF-β) in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Cells. 2024;13(15):1271.
24. Miyara M, Ito Y, Sakaguchi S. TREG-cell therapies for autoimmune rheumatic diseases. Nat Rev Rheumatol. 2014;10(9):543-51.
25. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3(3):253-7.
26. Lin X, Chen M, Liu Y, Guo Z, He X, Brand D, et al. Advances in distinguishing natural from induced Foxp3+ regulatory T cells. International journal of clinical and experimental pathology. 2013;6(2):116.
27. Ramsdell F. Foxp3 and natural regulatory T cells: key to a cell lineage? Immunity. 2003;19(2):165-8.
28. Sakaguchi S, Miyara M, Costantino CM, Hafler DA. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010;10(7):490-500.
29. Murai M, Turovskaya O, Kim G, Madan R, Karp CL, Cheroutre H, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol. 2009;10(11):1178-84.
30. Lange P, Ahmed E, Lahmar ZM, Martinez FJ, Bourdin A. Natural history and mechanisms of COPD. Respirology. 2021;26(4):298-321.
31. Jones S. COPD-Pathology, Diagnosis, Treatment, and Future Directions: Pathology, Diagnosis, Treatment, and Future Directions: BoD–Books on Demand; 2024.
32. Ryu MH, Murphy S, Hinkley M, Carlsten C. COPD exposed to air pollution: a path to understand and protect a susceptible population. Chest. 2024;165(4):836-46.
33. Holtzman MJ, Byers DE, Alexander-Brett J, Wang X. The role of airway epithelial cells and innate immune cells in chronic respiratory disease. Nat Rev Immunol. 2014;14(10):686-98.
34. Bhat TA, Panzica L, Kalathil SG, Thanavala Y. Immune dysfunction in patients with chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2015;12(Supplement 2):S169-S75.
35. Butler A, Walton GM, Sapey E. Neutrophilic inflammation in the pathogenesis of chronic obstructive pulmonary disease. COPD. 2018;15(4):392-404.
36. Ponce-Gallegos MA, Ramírez-Venegas A, Falfán-Valencia R. Th17 profile in COPD exacerbations. Int J Chron Obstruct Pulmon Dis. 2017:1857-65.
37. Tesmer LA, Lundy SK, Sarkar S, Fox DA. Th17 cells in human disease. Immunol Rev. 2008;223(1):87-113.
38. Vargas-Rojas MI, Ramírez-Venegas A, Limón-Camacho L, Ochoa L, Hernández-Zenteno R, Sansores RH. Increase of Th17 cells in peripheral blood of patients with chronic obstructive pulmonary disease. Resp Med. 2011;105(11):1648-54.
39. Nathan SD, Lacasse V, Bell H, Sista P, Di Marino M, Bull T, et al. COPD associated pulmonary hypertension: A post hoc analysis of the PERFECT study. Pulmonary Circul. 2024;14(4):e12430.
40. Humbert M, Monti G, Brenot F, Sitbon O, Portier A, Grangeot-Keros L, et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Res Crit Care Med. 1995;151(5):1628-31.
41. Joppa P, Petrasova D, Stancak B, Tkacova R. Systemic inflammation in patients with COPD and pulmonary hypertension. Chest. 2006;130(2):326-33.
42. Gupta R. Study of Mineral Bone Disease and Cardiovascular Morbidity in Relation with Fibroblast Growth Factor 23 in Chronic Kidney Disease Patient Presenting to Sree Mookambika Institute of Medical Sciences: Sree Mookambika Institute of Medical Sciences, Kulasekharam; 2019.
43. Yang X, Huo B, Zhong X, Su W, Liu W, Li Y, et al. Imbalance between subpopulations of regulatory T cells in patients with acute exacerbation of COPD. COPD. 2017;14(6):618-25.
44. Hou J, Sun Y, Hao Y, Zhuo J, Liu X, Bai P, et al. Imbalance between subpopulations of regulatory T cells in COPD. Thorax. 2013;68(12):1131-9.
45. Qu X, Yi X, Zhong H, Ruan W, Huang D. Effect and mechanism of imbalance via Th9 cells and Th17/Treg cells in inflammatory and fibrotic phases of pulmonary fibrosis in mice. Biotechnology and Genetic Engineering Reviews. 2024;40(3):3007-17.
46. Li X-N, Pan X, Qiu D. Imbalances of Th17 and Treg cells and their respective cytokines in COPD patients by disease stage. International Journal of Clinical and Experimental Medicine. 2014;7(12):5324.
47. Zhu R, Xie X, Wang N, Chen L, Hong Y. The T helper type 17/regulatory T cell imbalance was associated with Ras‐GTP ase overexpression in patients with pulmonary hypertension associated with chronic obstructive pulmonary disease. Immunology. 2019;157(4):304-11.
48. Baroja ML, Lorre K, Van Vaeck F, Ceuppens JL. The anti-T cell monoclonal antibody 9.3 (anti-CD28) provides a helper signal and bypasses the need for accessory cells in T cell activation with immobilized anti-CD3 and mitogens. Cell Immunol. 1989;120(1):205-17.
49. Hautefort A, Girerd B, Montani D, Cohen-Kaminsky S, Price L, Lambrecht BN, et al. T-helper 17 cell polarization in pulmonary arterial hypertension. Chest. 2015;147(6):1610-20.
50. Turner JA, Stephen-Victor E, Wang S, Rivas MN, Abdel-Gadir A, Harb H, et al. Regulatory T cell-derived TGF-β1 controls multiple checkpoints governing allergy and autoimmunity. Immunity. 2020;53(6):1202-14. e6.
51. Hall JA, Pokrovskii M, Kroehling L, Kim B-R, Kim SY, Wu L, et al. Transcription factor RORα enforces stability of the Th17 cell effector program by binding to a Rorc cis-regulatory element. Immunity. 2022;55(11):2027-43. e9.
52. Hill JA, Feuerer M, Tash K, Haxhinasto S, Perez J, Melamed R, et al. Foxp3 transcription-factor-dependent and-independent regulation of the regulatory T cell transcriptional signature. Immunity. 2007;27(5):786-800.
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How to Cite
1.
Jadidian N, Hazrati A, yazdchi A, Valizadeh H, Taban-Sadeghi MR, Ahmadi M, Mikaeili H. Th17/Treg Ratio in COPD Patients with Normal and High Pulmonary Arterial Hypertension. Iran J Allergy Asthma Immunol. 2026;:1-13.
