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The airway epithelium plays a key role in driving airway remodeling in severe asthma

As an initiator of airway remodeling, the airway epithelium plays a pivotal role in driving structural changes that contribute to the onset and progression of severe asthma1–4 

Home EpiFundamentals The airway epithelium plays a key role in driving airway remodeling in severe asthma

As an initiator of airway remodeling, the airway epithelium plays a pivotal role in driving structural changes that contribute to the onset and progression of severe asthma1–4

  • Airway remodeling describes heterogeneous structural changes occurring within the small and large airways of patients with asthma1,5,6
  • As the first line of defense against the external environment, the airway epithelium initiates airway remodeling in response to damage by releasing mediators including epithelial cytokines TSLP, IL-33, and IL-251,6,7
  • Epithelial cytokines play diverse, yet often overlapping, roles in airway remodeling through effects on structural and immune cells8
  • Airway remodeling can occur early in life before the onset of symptoms1,9,10; over time, accumulative remodeling results in structural changes that may impact clinical outcomes in severe asthma1,10
  • Unchecked airway remodeling ultimately results in fixed airflow limitation and contributes to lung function decline, severity, and chronicity of asthma1,4,9,11,12

Early identification of airway remodeling, before the onset of significant irreversible structural changes, may aid in clinical decision making and the achievement of disease remission as a goal in severe asthma care.9,13–15

References

1. Hough KP, et al. Front Med (Lausanne). 2020;7:191; 2. Yang Y, et al. Clin Respir J. 2021;15:1027–1045; 3. Beckett PA, Howarth PH. Thorax. 2003;58:163–174; 4. James AL, Wenzel S. Eur Respir J. 2007;30:134–155; 5. Hsieh A, et al. Front Physiol. 2023;14:1113100; 6. Varricchi G, et al. Allergy. 2022;77:3538–3552; 7. Samitas K, et al. Allergy. 2018;73:993–1002; 8. Gauvreau GM, et al. Allergy. 2023;78:402–417; 9. Thomas D, et al. Eur Respir J. 2022;60(5):2102583; 10. Fehrenbach H, et al. Cell Tissue Res. 2017;367:551–569; 11. Brightling CE, et al. Clin Exp Allergy. 2012;42:638–649; 12. Krings JG, et al. J Allergy Clin Immunol. 2021;148:752–762; 13. Zhang J, Dong L. J Thorac Dis. 2020;12:6090–6101; 14. Gras D, et al. Med Sci (Paris). 2011;27:959–965; 15. Gupta S, et al. Chest. 2009;136:1521–1528.  

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What is the clinical significance of airway remodeling in asthma?

Clinically, airway remodeling and resulting structural changes have implications for the severity of asthma, lung function decline, the risk of future exacerbations, and may be associated with asthma fatality.4,12 As a longitudinal process, airway remodeling is thought to also play a part in the chronicity of asthma.1,10,11

Unchecked airway remodeling results in fixed airflow limitation.1,11 Early identification of airway remodeling, before the onset of significant irreversible structural changes, may therefore aid in clinical decision making and improve disease outcomes in patients with asthma.13–15

The physiology of airway remodeling

Tissue remodeling is a normal physiological response necessary for the resolution of transient cell and tissue damage.10 In patients with asthma, this response is aberrant owing to contributing factors such as chronic airway inflammation and epithelial abnormalities.16,17 Improper repair in the face of recurrent damage can therefore lead to pathological airway remodeling.1,10,18

Airway remodeling describes structural changes occurring within the small and larger airways of patients with asthma.1,5,6 Physiological changes include epithelial disruption, goblet cell hyperplasia and submucosal gland enlargement, thickening and fibrosis of the subepithelial matrix, angiogenesis, and increased airway smooth muscle (ASM) mass.5,6

Whether airway remodeling is progressive or associated with disease progression has not been definitively proven19; however, it is thought that airway remodeling is a continuous process, often occurring early in life and persisting through to adulthood.1,3,20,21 Early structural changes are thought to predispose individuals to developing asthma, possibly by affecting structural development of the lungs.10 Cumulative remodeling throughout life can then manifest in the significant structural changes seen in severe asthma.22 Like inflammation, airway remodeling in asthma is heterogeneous5,11,13 and may contribute to the variability seen in asthma phenotypes and endotypes.13 The true heterogeneity of airway remodeling in asthma may not be fully understood; most studies of changes occurring in the small airways are carried out in cases of fatal asthma, which may not be representative of the full spectrum of asthma phenotypes.5,23

Functionally, cumulative airway remodeling leads to airflow limitation due to fixed airflow obstruction and mucus plugging.1,11 Increased deposition of extracellular matrix (ECM) components such as collagen in the basement membrane, lamina propria, and submucosa contributes to thickening and stiffening of the airway walls.1,6 Increased ASM mass, due to ASM hypertrophy and hyperplasia, also contributes to altered airway structure and functional dynamics.4,6 Excessive production of mucus, mediated by goblet cell hyperplasia and hyperplasia of the mucous glands,24 can ultimately lead to the formation of mucus plugs resulting in impaired airflow.25

While the lower airways show the most extensive structural changes in asthma, evidence also suggests that remodeling of the upper airways may play a role in asthma pathophysiology.7,26 For example, basement reticular layer thickening has been shown in the nasal passage of patients with asthma.26 The existence of such relationships has led to the concept of ‘united airways disease.’7,27 Visit The importance of the epithelium and epithelial cytokines in uniting upper and lower airway diseases to learn more about united airways disease in asthma and beyond.

Figure adapted from Hsieh A, et al. Front Physiol 2023;14:1113100
Figure adapted from Hsieh A et al. Front Physiol. 2023;14:1113100

What triggers airway remodeling in asthma?

As the first line of defense against the external exposome, the airway epithelium acts as an initiation point for airway remodeling.1,28 Exposure to environmental triggers can disrupt the epithelium.29 A variety of environmental triggers are implicated in airway remodeling, including exposure to allergens, viruses, and air pollutants.1 Early-life exposure to viruses and air pollutants may be particularly important in the initiation of airway remodeling and asthma.10,30 To find out more about environmental triggers and their role in asthma, read Role of the epithelium in asthma.

In response to transient, persistent, or prolonged damage, the epithelium can initiate airway remodeling through the induction of inflammation.10,31 In the case of persistent or prolonged damage, failed resolution of inflammation leads to aberrant self-repair and clinical symptoms.1–3,10,31

Progression of airway remodeling in the asthmatic lung

Progression of airway remodeling in the asthmatic lung

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Although inflammation can drive airway remodeling, remodeling can also occur independently of inflammation.1 Bronchoconstriction, which also occurs in response to environmental triggers, can promote remodeling in the absence of inflammation.32 During bronchoconstriction, cells of the airways are exposed to excessive physical forces, stimulating mechanical signaling and inducing a remodeling response.33 Many patients with asthma exhibit an enhanced bronchoconstrictive response to environmental stimuli, otherwise known as airway hyperresponsiveness.34,35 Repeated bronchoconstriction associated with existing airway hyperresponsiveness could, therefore, exacerbate remodeling processes independently of inflammation.1,24,32 To learn more about airway hyperresponsiveness and its relationship with airway remodeling, visit Airway hyperresponsiveness in severe asthma.

How does the epithelium orchestrate remodeling in asthma?

In response to damaging environmental exposures, the airway epithelium releases an array of mediators including epithelial cytokines, growth factors, and matrix metalloproteinases (MMPs).7 The downstream actions of these mediators drive the structural changes associated with airway remodeling.1,6

Epithelial cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25, are first responders to external insults.29,36 These cytokines have varying reported contributions to airway remodeling through effects on lung fibroblasts and ASM in vitro:

  • TSLP, IL-33, and IL-25 induce the expression of collagen by lung fibroblasts37–42
  • IL-25 promotes lung fibroblast proliferation43
  • TSLP promotes migration of ASM cells,44 and IL-33 directs ASM repair45

Download the Airway remodeling and epithelial cytokines asset to learn more about the histological features of airway remodeling and their association with epithelial cytokines

Epithelial-to-mesenchymal transition (EMT) is a key feature of airway remodeling, whereby crosstalk between the epithelium and fibroblast-like mesenchymal cells promotes basement membrane thickening, subepithelial fibrosis, and smooth muscle hyperplasia in response to recurring damage.1,7,18,46 TSLP has been shown to induce this process in vitro by upregulating the expression of transforming growth factor-beta (TGF-β), a key regulator of EMT.46,47 Currently, there is no published evidence to suggest that IL-33 and IL-25 drive EMT in humans. Aside from epithelial cells, other sources of TGF-β in EMT include macrophages and eosinophils.6 In addition, growth factors such as vascular endothelial growth factor (VEGF) and MMPs can also be released by the epithelium and play a role in EMT.48,49

In addition to actions on structural cells, epithelial cytokines act on immune cells to varying extents50; downstream effects may propagate further remodeling changes.6,51 As described in Airway hyperresponsiveness in severe asthma, mast cells that have localized to the ASM release epithelial cytokines that may also drive structural changes through interaction with ASM. Mast cell release of mediators, including TSLP and IL-33, can drive bronchoconstriction and increased
ASM mass.45,52–62

As a consequence of airway remodeling, epithelial disruption may result in abnormal epithelium-mediated immune responses, which drives a positive feedback loop to further perpetuate airway remodeling.2,29,63

To learn more about the role of airway remodeling and EMT in the upper airway, please read 'Chronic rhinosinusitis and the central role of the nasal epithelium'.

Epithelial cytokines can play diverse, yet often overlapping, roles in airway remodelling in asthma

Epithelial cytokines can play diverse, yet often overlapping, roles in airway remodeling in asthma

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How is airway remodeling assessed?

The current gold standard method for the assessment of airway remodeling involves the use of direct techniques such as bronchial biopsy, although a variety of non-invasive techniques are also available to clinicians and researchers.1,64 Measurement of airway remodeling can be used to complement the assessment of asthma severity and monitor disease progression.13,19,65 Despite the availability of investigative techniques, advancements in the understanding of airway remodeling in asthma can be made challenging by factors such as the prolonged timeframe of airway remodeling progression in humans.66 Modern approaches such as novel radiological technologies, single-cell RNA sequencing, and air-liquid interface (ALI) models may help to address these issues and permit interrogation of mechanisms underlying airway remodeling and the identification of biomarkers for improved phenotyping and endotyping of patients.6,13,66–68

Techniques for assessing airway remodelling in asthma

Techniques for assessing airway remodeling in asthma

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Download the Radiological assessment of airway remodeling asset to learn more about the benefits, limitations, and clinical correlates of radiological techniques available for the assessment of airway remodeling in asthma.

The content for this module was created with the support of Professor Pascal Chanez and Professor Gilda Varricchi.

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Airway hyperresponsiveness in severe asthma

Professor Bruce Levy, MD

To learn more about airway hyperresponsiveness in severe asthma

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References

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