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

As an initiator of airway remodelling, the airway epithelium plays a pivotal role in driving structural changes that contribute to the onset and progression of severe asthma.1–4

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

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

  • Airway remodelling describes heterogeneous structural changes occurring within the small and large airways of patients with asthma1,5,6
  • As the first line of defence against the external environment, the airway epithelium initiates airway remodelling 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 remodelling through effects on structural and immune cells8
  • Airway remodelling can occur early in life before the onset of symptoms;1,9,10 over time, accumulative remodelling results in structural changes that may impact clinical outcomes in severe asthma1,10
  • Unchecked airway remodelling ultimately results in fixed airflow limitation and contributes to lung function decline, severity, chronicity and fatality1,4,9,11,12

Early identification of airway remodelling, 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 care9,13–15

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;77:3535–3552; 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;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 remodelling in asthma?

Clinically, airway remodelling has implications for the severity of asthma, lung function decline, the risk of future exacerbations and asthma fatality.4,12 As a longitudinal process, airway remodelling is thought to also play a part in the chronicity of asthma.1,10,11

Unchecked airway remodelling results in fixed airflow limitation.1,11 Early identification of airway remodelling, 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 remodelling

Tissue remodelling is a normal physiological response necessary for the resolution of transient cell and tissue damage.10 In patients with asthma this response is aberrant due 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 remodelling.1,10,18

Airway remodelling 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

Airway remodelling is a continuous process, often occurring early in life and persisting through to adulthood.1,3,19,20 Early structural changes are thought to predispose individuals to developing asthma, possibly by affecting structural development of the lungs.10 Cumulative remodelling throughout life can then manifest in the significant structural changes seen in severe asthma.21 Like inflammation, airway remodelling in asthma is heterogeneous5,11,13 and may contribute to the variability seen in asthma phenotypes and endotypes.13 The true heterogeneity of airway remodelling 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.5,22

Functionally, cumulative airway remodelling 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,23 can ultimately lead to the formation of mucus plugs resulting in impaired airflow.24

While the lower airways show the most extensive structural changes in asthma, evidence also suggests that remodelling of the upper airways may play a role in asthma pathophysiology.7,25 For example, basement reticular layer thickening has been shown in the nasal passage of patients with asthma.25 The existence of such relationships has led to the concept of ‘united airway disease’.7,26 Visit The importance of the epithelium and epithelial cytokines in uniting upper and lower airway diseases to learn more about united airway disease in asthma and beyond.

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

What triggers airway remodelling in asthma?

As the first line of defence against the external exposome, the airway epithelium acts as an initiation point for airway remodelling.1,27 Exposure to environmental triggers can disrupt the epithelium.28 A variety of environmental triggers are implicated in airway remodelling, 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 remodelling and asthma.10,29 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 remodelling through the induction of inflammation.10,30 In the case of persistent or prolonged damage, failed resolution of inflammation leads to aberrant self-repair and clinical symptoms.1–3,10,30

Irreversible remodelling infographic

Progression of airway remodelling in the asthmatic lung

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Although inflammation can drive airway remodelling, remodelling can also occur independently of inflammation.1 Bronchoconstriction, which also occurs in response to environmental triggers, can promote remodelling in the absence of inflammation.31 During bronchoconstriction, cells of the airways are exposed to excessive physical forces, stimulating mechanical signalling and inducing a remodelling response.32 Many patients with asthma exhibit an enhanced bronchoconstrictive response to environmental stimuli, otherwise known as airway hyperresponsiveness.33,34 Repeated bronchoconstriction associated with existing airway hyperresponsiveness could, therefore, exacerbate remodelling processes independently of inflammation.1,23,31 To learn more about airway hyperresponsiveness and its relationship with airway remodelling, visit Airway hyperresponsiveness in severe asthma.

How does the epithelium orchestrate remodelling 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 remodelling.1,6

Epithelial cytokines, thymic stromal lymphopoietin (TSLP), interleukin (IL)-33 and IL-25, are first responders to external insults.28,35 These cytokines have varying reported contributions to airway remodelling through effects on lung fibroblasts and ASM in vitro:

  • TSLP, IL-33 and IL-25 induce the expression of collagen by lung fibroblasts36–41
  • IL-25 promotes lung fibroblast proliferation42
  • TSLP promotes migration of ASM cells,43 and IL-33 directs ASM repair44

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

Epithelial-to-mesenchymal transition (EMT) is a key feature of airway remodelling, 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.1,7,18,45 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.45,46 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.47,48

In addition to actions on structural cells, epithelial cytokines act on immune cells to varying extents;49 downstream effects may propagate further remodelling changes.6,50 As described in Airway hyperresponsiveness in severe asthma,  mast cells that have localised 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.44,51–61

As a consequence of airway remodelling, epithelial disruption may result in abnormal epithelium-mediated immune responses, which drives a positive feedback loop to further perpetuate airway remodelling.2,28,61

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

Remodelling - Role of epithelial cytokines infographic

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

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How is airway remodelling assessed?

The current gold standard method for the assessment of airway remodelling involves the use of direct techniques such as bronchial biopsy, although a variety of non-invasive techniques are also available to clinicians and researchers.1,63 Measurement of airway remodelling can be used to complement the assessment of asthma severity and monitor disease progression.13,64,65 Modern approaches such as single-cell RNA sequencing and air-liquid interface (ALI) models will permit interrogation of mechanisms underlying airway remodelling and the identification of biomarkers for improved phenotyping and endotyping of patients.6,13,66,67

Assessment of remodelling infographic

Techniques for assessing airway remodelling in asthma

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Download the Radiological assessment of airway remodelling asset to learn more about the benefits, limitations and clinical correlates of radiological techniques available for the assessment of airway remodelling 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, visit the 'Airway hyperresponsiveness in severe asthma' page.

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References

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