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image of Asthma Pathogenesis: Clinical Expression, Molecular Mechanisms, and Risk Factors

Abstract

With variable airflow obstruction, bronchial hyperresponsiveness, and persistent inflammation, asthma is a chronic respiratory disorder characterized by its complex pathogenesis. This review further explores the complex pathogenesis of asthma by examining various clinical phenotypes, molecular mechanisms, and multifactorial risk factors. Asthma shows phenotypic heterogeneity clinically, often classified along immune profiles and biomarkers with eosinophilic and non-eosinophilic endotypes. At the molecular level, asthma is manifested as dysregulated immune responses, primarily Th2-mediated and, in some instances, Th17-mediated inflammation using cytokines IL-4, IL-5, IL-13, and IL-17. Furthermore, the airway remodelling layer, consisting of epithelial-mesenchymal transition, goblet cell hyperplasia, and subepithelial fibrosis, facilitates this progression. Genetic susceptibility, epigenetic changes, and alterations in gut microbiota contribute to immune dysregulation, while environmental triggers like allergens, pollutants, and infections worsen the disease. The genetic predisposition, environmental influences, and immune regulation are shown to be inextricably intertwined, emphasizing the need to use a phenotype- and endotype-based approach in the hope of providing better personalized care for asthma and saving the world from its burden.

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2025-10-24
2025-12-18

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References

  1. Sunkara K. Mehta M. Satija S. Dhanjal D.S. Sharma P. Shukla S.D. Shastri M. Zacconi F.C. Dua K. Allam V.S.R.R. An introduction to respiratory diseases and an emerging need for efficient drug delivery systems. Adv. Drug Deliv. Strateg. Target. Chronic Inflamm. Lung Dis. Springer 2022 Jan 1 24 10.1007/978‑981‑16‑4392‑7_1
    [Google Scholar]
  2. Subbarao P. Mandhane P.J. Sears M.R. Asthma: Epidemiology, etiology and risk factors. CMAJ 2009 181 9 E181 E190 10.1503/cmaj.080612 19752106
    [Google Scholar]
  3. Lemanske R.F. Jr Busse W.W. Asthma: Clinical expression and molecular mechanisms. J. Allergy Clin. Immunol. 2010 125 2 S95 S102 10.1016/j.jaci.2009.10.047 20176271
    [Google Scholar]
  4. Moskvin S.V. Khadartsev A.A. Methods of effective low-level laser therapy in the treatment of patients with bronchial Asthma. Biomedicine (Taipei) 2020 10 1 1 20 10.37796/2211‑8039.1000 33854908
    [Google Scholar]
  5. Ludviksdottir D. Diamant Z. Alving K. Bjermer L. Malinovschi A. Clinical aspects of using exhaled NO in Asthma diagnosis and management. Clin. Respir. J. 2012 6 4 193 207 10.1111/crj.12001 22898078
    [Google Scholar]
  6. Mitchell I. Govias G. Comorbidities in Asthma. Asthma Education Springer 2021 291 331 10.1007/978‑3‑030‑77896‑5_9
    [Google Scholar]
  7. Jones S.A. Jones S.A. A. Jones S. COPD - Pathology, Diagnosis, Treatment, and Future Directions. Diagnosis, Treatment, and Future Directions. London: IntechOpen; 2024 Jun. 10.5772/intechopen.1001502
    [Google Scholar]
  8. Gupta S. Lodha R. Kabra S.K. Asthma, GERD and obesity: Triangle of inflammation. Indian J. Pediatr. 2018 85 10 887 892 10.1007/s12098‑017‑2484‑0 29127618
    [Google Scholar]
  9. Reddel H.K. FitzGerald J.M. Bateman E.D. Bacharier L.B. Becker A. Brusselle G. Buhl R. Cruz A.A. Fleming L. Inoue H. Ko F.W. Krishnan J.A. Levy M.L. Lin J. Pedersen S.E. Sheikh A. Yorgancioglu A. Boulet L.P. GINA 2019: A fundamental change in Asthma management. Eur. Respir. J. 2019 53 6 1901046 10.1183/13993003.01046‑2019 31249014
    [Google Scholar]
  10. Alhamdan F. Identification of underlying molecular mechanisms of obesity-associated Asthma [doctoral thesis]. Marburg (Germany): Philipps-University Marburg; 2021 10.17192/Z2022.0005
    [Google Scholar]
  11. Striz I. New insights into the pathophysiology and therapeutic targets of Asthma and comorbid chronic rhinosinusitis with or without nasal polyposis. Clin Sci 2023 137 9 727 753 10.1042/CS20190281
    [Google Scholar]
  12. Kuruvilla M.E. Vanijcharoenkarn K. Levy J.M. The role of mast cells in aspirin-exacerbated respiratory disease (AERD) pathogenesis: implications for future therapeutics. J Asthma Allergy 2020 13 463 470 10.2147/JAA.S237463
    [Google Scholar]
  13. Ramirez G.A. Yacoub M.R. Ripa M. Mannina D. Cariddi A. Saporiti N. Ciceri F. Castagna A. Colombo G. Dagna L. Eosinophils from physiology to disease: A comprehensive review. BioMed Res. Int. 2018 2018 1 28 10.1155/2018/9095275 29619379
    [Google Scholar]
  14. Trivedi A Biomarkers in Asthma: State of the art. Allergy Asthma Clin Immunol 2018 12 4 1 10.1186/s40733‑018‑0047‑4
    [Google Scholar]
  15. Ali N.H. Rehman S. Naqvi M. Gulati K. Ray A. Periostin: A potential biomarker and therapeutic target in pulmonary diseases. J Pharm Pharm Sci 2022 25 137 148 10.18433/jpps32306 35379385
    [Google Scholar]
  16. Laidlaw T.M. Pathogenesis of NSAID-induced reactions in aspirin-exacerbated respiratory disease. World J. Otorhinolaryngol. Head Neck Surg. 2018 4 3 162 168 10.1016/j.wjorl.2018.08.001 30506046
    [Google Scholar]
  17. Stahl G. Bagot J.L. What should be the place of the tuberculinic chronic reactive mode in 21 st century homeopathic practice? Rev. Homeopath. 2021 12 3 e21 e29 10.1016/j.revhom.2021.07.026
    [Google Scholar]
  18. Semprini R. Periostin - A biomarker in adults with Asthma. Te Herenga Waka—Victoria University of Wellington 2019 10.26686/wgtn.17136371.v1
    [Google Scholar]
  19. Şenel F.Ç. Yorgancioğlu A. Cruz A.A. Does rhinitis pharmacotherapy improve control of comorbid Asthma? Challenges in Rhinology 2020 Oct 416 427 10.1007/978‑3‑030‑50899‑9_41
    [Google Scholar]
  20. Zhang X. Xia T. Lai Z. Zhang Q. Guan Y. Zhong N. Uncontrolled Asthma phenotypes defined from parameters using quantitative CT analysis. Eur. Radiol. 2019 29 6 2848 2858 10.1007/s00330‑018‑5913‑1 30617489
    [Google Scholar]
  21. Ito J.T. Lourenço J.D. Righetti R.F. Tibério I.F.L.C. Prado C.M. Lopes F.D.T.Q.S. Extracellular matrix component remodeling in respiratory diseases: What has been found in clinical and experimental studies? Cells 2019 8 4 342 10.3390/cells8040342 30979017
    [Google Scholar]
  22. Garg R. Piplani M. Singh Y. Joshi Y. Epidemiology, pathophysiology, and pharmacological status of Asthma. Curr. Respir. Med. Rev. 2022 18 4 247 258 10.2174/1573398X18666220526164329
    [Google Scholar]
  23. Stern J. Pier J. Litonjua A.A. Asthma epidemiology and risk factors. Semin Immunopathol. 2020 42 1 5 15 10.1007/s00281‑020‑00785‑1
    [Google Scholar]
  24. Chatkin J. Correa L. Santos U. External environmental pollution as a risk factor for Asthma. Clinic Rev Allerg Immunol 2022 62 72 89 10.1007/s12016‑020‑08830‑5
    [Google Scholar]
  25. Chen Q. Nian S. Ye Y. Liu D. Yu H. Xiong H. Pan B. Xiao L. Fan C. Yuan Q. The emerging roles of T helper cell subsets and cytokines in severe neutrophilic Asthma. Inflammation 2022 45 3 1007 1022 10.1007/s10753‑021‑01598‑6 34825300
    [Google Scholar]
  26. Alobaidi A.H. Alsamarai A.M. Alsamarai M.A. Inflammation in Asthma pathogenesis: Role of t cells, macrophages, epithelial cells and type 2 inflammation. Antiinflamm. Antiallergy Agents Med. Chem. 2021 20 4 317 332 10.2174/1871523020666210920100707 34544350
    [Google Scholar]
  27. Bergantini L, d’Alessandro M, Cameli P, Pianigiani T, Fanetti M, Sestini P, Bargagli E. Follicular T helper and Breg cell balance in severe allergic Asthma before and after omalizumab therapy. Mol Diagn Ther. 2021 25 5 593 605 10.1183/13993003.congress‑2021.OA2831
    [Google Scholar]
  28. Yao Y. Chen C.L. Yu D. Liu Z. Roles of follicular helper and regulatory T cells in allergic diseases and allergen immunotherapy. Allergy 2021 76 2 456 470 10.1111/all.14639 33098663
    [Google Scholar]
  29. Zhang N. Xu J. Jiang C. Lu S. Neuro-immune regulation in inflammation and airway remodeling of allergic Asthma. Front. Immunol. 2022 13 894047 10.3389/fimmu.2022.894047 35784284
    [Google Scholar]
  30. Huang Y. Research advances in airway remodeling in Asthma: A narrative review. Ann Transl Med 2022 10 18 1023 10.21037/atm‑22‑2835
    [Google Scholar]
  31. Jackson D.J. Gern J.E. Rhinovirus infections and their roles in Asthma: Etiology and exacerbations. J. Allergy Clin. Immunol. Pract. 2022 10 3 673 681 10.1016/j.jaip.2022.01.006 35074599
    [Google Scholar]
  32. Hirahara K. Aoki A Nakamura T Pathogenic helper T cells. Allergol Int 2021 70 2 169 173 10.1016/j.alit.2021.02.001
    [Google Scholar]
  33. Bryant N. T-cell responses in Asthma exacerbations. Ann Allergy Asthma Immunol 2022 129 6 709 718 10.1016/j.anai.2022.07.027
    [Google Scholar]
  34. Varricchi G, Ferri S, Pepys J, Poto R, Spadaro G, Nappi E, Paoletti G, Virchow JC, Heffler E, Canonica WG. Biologics and airway remodeling in severe Asthma Allergy 2022 77 12 3538-3552 10.1111/all.15473
    [Google Scholar]
  35. Varricchi G. Ferri S. Pepys J. Poto R. Spadaro G. Nappi E. Paoletti G. Virchow J.C. Heffler E. Canonica W.G. Biologics and airway remodeling in severe Asthma. Allergy 2022 77 12 3538 3552 10.1111/all.15473 35950646
    [Google Scholar]
  36. Joseph C. Pathobiology of airway remodeling in Asthma: The emerging role of integrins. J Asthma Allergy 2022 15 595 610 10.2147/JAA.S267222 35592385
    [Google Scholar]
  37. Khalfaoui L. Airway smooth muscle in contractility and remodeling of Asthma: potential drug target mechanisms. Expert Opin Ther Targets. 2023 27 1 19 29 10.1080/14728222.2023.2177533
    [Google Scholar]
  38. Moraes-Ferreira R. Brandao-Rangel M.A.R. Gibson-Alves T.G. Silva-Reis A. Souza-Palmeira V.H. Aquino-Santos H.C. Frison C.R. Oliveira L.V.F. Albertini R. Vieira R.P. Physical training reduces chronic airway inflammation and mediators of remodeling in Asthma. Oxid. Med. Cell. Longev. 2022 2022 1 5037553 10.1155/2022/5037553 36312895
    [Google Scholar]
  39. Holgate S.T. Airway inflammation and remodeling in Asthma: current concepts. Mol. Biotechnol. 2002 22 2 179 190 10.1385/MB:22:2:179 12405265
    [Google Scholar]
  40. Meo S.A. Salih M.A. Alkhalifah J.M. Alsomali A.H. Almushawah A.A. Environmental pollutants particulate matter (PM2.5, PM10), Carbon Monoxide (CO), Nitrogen dioxide (NO2), Sulfur dioxide (SO2), and Ozone (O3) impact on lung functions. J. King Saud Univ. Sci. 2024 36 7 103280 10.1016/j.jksus.2024.103280
    [Google Scholar]
  41. Mthembu N. Ikwegbue P. Brombacher F. Hadebe S. Respiratory viral and bacterial factors that influence early childhood Asthma. Front. Allergy 2021 2 692841 10.3389/falgy.2021.692841 35387053
    [Google Scholar]
  42. Raby K.L. Michaeloudes C. Tonkin J. Chung K.F. Bhavsar P.K. Mechanisms of airway epithelial injury and abnormal repair in Asthma and COPD. Front. Immunol. 2023 14 1201658 10.3389/fimmu.2023.1201658 37520564
    [Google Scholar]
  43. Listyoko A.S. Okazaki R. Harada T. Inui G. Yamasaki A. Impact of obesity on airway remodeling in Asthma: Pathophysiological insights and clinical implications. Front. Allergy 2024 5 1365801 10.3389/falgy.2024.1365801 38562155
    [Google Scholar]
  44. Singla A. Reuter S. Taube C. Peters M. The molecular mechanisms of remodeling in Asthma, COPD and IPF with a special emphasis on the complex role of Wnt5A. Inflamm Res. 2023 72 3 577 588 10.1007/s00011‑023‑01692‑5
    [Google Scholar]
  45. Hsieh A. Assadinia N. Hackett T.L. Airway remodeling heterogeneity in Asthma and its relationship to disease outcomes. Front. Physiol. 2023 14 1113100 10.3389/fphys.2023.1113100 36744026
    [Google Scholar]
  46. Chetty A. Targeting airway smooth muscle hypertrophy in Asthma: An approach whose time has come. J Asthma Allergy 2021 14 539 556 10.2147/JAA.S280247
    [Google Scholar]
  47. Antczak A. Domańska-Senderowska D. Górski P. Pastuszak-Lewandoska D. Nielepkowicz-Goździńska A. Szewczyk K. Kurmanowska Z. Kiszałkiewicz J. Brzeziańska- Lasota E. Analysis of changes in expression of IL-4/IL-13/STAT6 pathway and correlation with the selected clinical parameters in patients with atopic Asthma. Int. J. Immunopathol. Pharmacol. 2016 29 2 195 204 10.1177/0394632015623794 26781462
    [Google Scholar]
  48. Zhou B. Liu H. Jia X. The role and mechanisms of traditional chinese medicine for airway inflammation and remodeling in Asthma: Overview and progress. Front. Pharmacol. 2022 13 917256 10.3389/fphar.2022.917256 35910345
    [Google Scholar]
  49. Chen C. Y. Personalized medicine in severe Asthma: From biomarkers to biologics. Int J Mol Sci. 2023 25 1 182 10.3390/ijms25010182
    [Google Scholar]
  50. Pelaia C. Crimi C. Vatrella A. Tinello C. Terracciano R. Pelaia G. Molecular targets for biological therapies of severe Asthma. Front. Immunol. 2020 11 603312 10.3389/fimmu.2020.603312 33329598
    [Google Scholar]
  51. Qin K. Xu B. Pang M. The functions of CD4 T-helper lymphocytes in chronic obstructive pulmonary disease. Acta Biochim Biophys Sin 2021 54 2 173 178 10.3724/abbs.2021009
    [Google Scholar]
  52. Ji T. Li H. T-helper cells and their cytokines in pathogenesis and treatment of Asthma. Front. Immunol. 2023 14 1149203 10.3389/fimmu.2023.1149203 37377958
    [Google Scholar]
  53. Beuther D.A. Murphy K.R. Zeiger R.S. Wise R.A. McCann W. Reibman J. George M. Gilbert I. Eudicone J.M. Gandhi H.N. Ross M. Coyne K.S. Chipps B. The Asthma impairment and risk Questionnaire (AIRQ) control level predicts future risk of Asthma exacerbations. J. Allergy Clin. Immunol. Pract. 2022 10 12 3204 3212.e2 10.1016/j.jaip.2022.08.017 35998877
    [Google Scholar]
  54. Wenzel S.E. Severe adult Asthmas: Integrating clinical features, biology, and therapeutics to improve outcomes. Am. J. Respir. Crit. Care Med. 2021 203 7 809 821 10.1164/rccm.202009‑3631CI 33326352
    [Google Scholar]
  55. Habib N. Pasha M. A. Tang D. D. Current understanding of Asthma pathogenesis and biomarkers. Cells 2022 11 17 2764 10.3390/cells11172764
    [Google Scholar]
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Asthma Pathogenesis: Clinical Expression, Molecular Mechanisms, and Risk Factors
Bentham Science Publishers ; https://doi.org/10.2174/011573398X386472250930122954
/content/journals/crmr/10.2174/011573398X386472250930122954
/content/journals/crmr/10.2174/011573398X386472250930122954
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  • Article Type:     Review Article
Keywords: immune dysregulation ; Asthma pathogenesis ; molecular mechanisms ; clinical phenotypes ; Th2 and Th17 inflammation ; bronchial hyper-responsiveness

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