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Airway immunobiology and remodeling

TL;DR — Asthma is produced by interacting epithelial, immune, neural and structural programs rather than one inflammatory pathway. In type-2-high disease, epithelial alarmins activate dendritic cells, Th2 cells and ILC2s; IL-4/IL-13 promote IgE biology, mucus and FeNO, while IL-5 sustains eosinophils (Fahy 2015, PMID 25534623). Type-2-low labels cover several incompletely resolved states—neutrophilic, obesity-associated and paucigranulocytic disease—and can be changed by corticosteroid exposure or sampling method (Hudey 2020, PMID 33160187). Remodeling includes epithelial injury, basement-membrane-zone thickening, mucus metaplasia, angiogenesis and increased airway-smooth-muscle mass, but structure and inflammation do not advance in lockstep (Fehrenbach 2017, PMID 28190087). CT-visible mucus plugs provide a measurable bridge between inflammation and fixed obstruction: in severe asthma, plug burden was linked to eosinophilia and airflow limitation (Dunican 2018, PMID 29400693). Biologics prove that several pathways are therapeutically causal, but they do not establish a single upstream cause of asthma.

The airway as an interacting system

The useful unit is not “inflammation” alone. Asthma expression emerges from five coupled compartments:

Compartment Principal components Asthma-relevant outputs
Epithelium Ciliated, secretory, basal and tuft cells; barrier junctions Alarmins, mucus, antiviral signaling, repair and sensory coupling (Holgate 2007, PMID 18073119)
Innate immunity Dendritic cells, mast cells, eosinophils, neutrophils, macrophages, ILCs Rapid allergen/virus responses, granulocyte recruitment and mediator release
Adaptive immunity Th2, Th17, regulatory and memory lymphocytes; B cells Cytokine polarization, IgE, durable antigen memory
Structural tissue Smooth muscle, fibroblasts, myofibroblasts, vessels and extracellular matrix Hyperresponsiveness, narrowing, fibrosis and altered airway mechanics (Hirota 2013, PMID 24008953)
Neural/vascular interface Sensory and autonomic nerves, neuropeptides, microvasculature Cough, bronchoconstriction, edema and symptom perception

The compartments are bidirectional: epithelial damage changes immune recruitment; cytokines change epithelial differentiation; bronchoconstriction itself can impose mechanical stress; remodeling then alters how a future inflammatory episode changes airflow (Banno 2020, PMID 32369100).

Epithelial initiation and alarmins

Airway epithelium senses allergens with protease activity, viruses, smoke, ozone and other pollutants. Barrier dysfunction and cell stress release thymic stromal lymphopoietin (TSLP), IL-33 and IL-25, which are termed alarmins because they translate tissue perturbation into immune activation (Gauvreau 2020, PMID 31408015; Gauvreau 2023, PMID 36463491).

Alarmin Major downstream connections Human therapeutic evidence
TSLP Dendritic-cell priming, mast cells, ILC2 and Th2 amplification Tezepelumab reduces exacerbations across a broad severe-asthma population, with greater effects at higher type-2 markers (Menzies-Gow 2021, PMID 33979488)
IL-33 ST2 on ILC2, mast cells and other immune cells; can contribute to type-2 and some neutrophilic responses Astegolimab, an anti-ST2 antibody, has randomized severe-asthma evidence but did not reproduce the broad effect size of TSLP blockade (Kelsen 2021, PMID 33872652)
IL-25 Type-2 amplification through ILC2 and adaptive responses Strong preclinical biology; no established asthma biologic in routine use (Mitchell 2017, PMID 27818325)

“Upstream” is relative, not absolute. TSLP, IL-33 and IL-25 interact with each other and with viral interferon responses; distinct epithelial insults can therefore converge on partly shared cytokine networks (Toki 2020, PMID 31975538).

Type-2 inflammation

Type-2-high asthma is a treatment-relevant state rather than a synonym for allergic asthma. It can be driven by allergen-specific adaptive immunity, innate alarmin–ILC2 activation, or both (Fahy 2015, PMID 25534623).

Axis Core biology Accessible readout Intervention that tests causality
IgE/FcεRI Allergen-specific IgE loads mast cells and basophils; crosslinking releases bronchoconstrictors and cytokines Sensitization testing plus total/specific IgE Omalizumab reduces attacks in selected allergic asthma (Humbert 2005, PMID 15679715)
IL-5/eosinophil IL-5 supports eosinophil maturation, survival and trafficking; eosinophils release granule proteins, lipids and remodeling signals Blood/sputum eosinophils Mepolizumab and benralizumab reduce attacks in eosinophilic severe asthma (Pavord 2012, PMID 22901886; Bleecker 2016, PMID 27609408)
IL-4/IL-13 IgE class switching, epithelial nitric oxide, mucus differentiation, smooth-muscle effects FeNO, eosinophils and clinical atopy Dupilumab blocks IL-4Rα signaling and improves attacks and FEV1, strongest with type-2 markers (Castro 2018, PMID 29782217)
Epithelial type-2 transcriptome Coordinated epithelial genes induced by IL-13 Research gene-expression signatures; FeNO/periostin are imperfect surrogates Corticosteroid response differs across transcriptomic patterns (Woodruff 2007, PMID 17898169)

The classic “Th2-high/Th2-low” airway transcriptomic distinction emerged from bronchial epithelial gene expression and was later measurable in sputum, creating an endotype that predicted corticosteroid responsiveness better than symptoms alone (Choy 2011, PMID 21187436; Peters 2014, PMID 24075231).

Blood eosinophils and FeNO sample different parts of type-2 biology. Either can be high alone; corticosteroids lower both but not identically. The markers should therefore be treated as continuous, time-varying risk measures rather than binary proof of a stable endotype (Gans 2020, PMID 31678040).

Mucus: an active mechanism, not just a symptom

IL-13 shifts epithelial differentiation toward secretory cells and increases MUC5AC relative to healthy ciliated-cell programs. Dehydration, mucin concentration and oxidative cross-linking can transform secretion into persistent airway plugs.

In CT research, mucus plugs were present across asthma severity but were concentrated in patients with eosinophilia and lower airflow; plug scoring linked a structural image phenotype to type-2 inflammation and obstruction (Dunican 2018, PMID 29400693).

Longitudinal imaging showed that plugs can persist and that changes in plug burden track changes in airflow, supporting a dynamic—not purely scar-like—component of obstruction (Tang 2022, PMID 35104436).

Mucus plugging can produce ventilation defects and severe airflow limitation without proportionate symptoms. It is a candidate intermediate endpoint, but CT radiation, scoring labor and incomplete standardization currently limit routine serial use.

Airway hyperresponsiveness

Airway hyperresponsiveness (AHR) is excessive narrowing to stimuli that produce little response in healthy airways. It reflects several interacting mechanisms:

  • increased or hypercontractile smooth muscle;
  • inflammatory mediator effects on muscle and nerves;
  • epithelial barrier and mediator abnormalities;
  • reduced baseline airway caliber and altered parenchymal load;
  • mucus and edema amplifying small reductions in radius.

The nonlinear relationship between airway radius and resistance means modest wall thickening or contraction can produce large airflow change. AHR is therefore a systems phenotype, not evidence for one immune pathway (Holgate 2008, PMID 18498538).

Bronchoconstriction may also contribute mechanically to remodeling. Whether preventing contraction independently prevents long-term structural change remains unresolved.

Remodeling: components and measurement

Airway remodeling is a collective term, not a single lesion.

Component Measurement Interpretation problem
Basement-membrane-zone thickening/subepithelial collagen Bronchial biopsy Sampling is proximal and small; thickness does not directly equal whole-airway fibrosis
Airway smooth-muscle mass Biopsy morphometry; indirect CT measures Hyperplasia versus hypertrophy varies by study and severity (Black 2004, PMID 15107302)
Goblet-cell metaplasia and mucus glands Biopsy, sputum mucins, CT plug score Secretion is dynamic; plugs can change without permanent structural reversal
Angiogenesis and vascular leak Biopsy vascular density, imaging research Relationship to symptoms and treatment response is incompletely standardized
Wall thickening and air trapping Quantitative CT, oscillometry and washout Resolution, lung volume and airway-size normalization alter estimates (Donovan 2023, PMID 36691759)
Fixed airflow limitation Post-bronchodilator spirometry Integrates remodeling, dysanapsis, mucus, aging and smoking; not a direct histologic measure

Remodeling can appear early and is not confined to the most severe disease. Yet the degree of inflammation, biopsy change, AHR and fixed obstruction correlates imperfectly between individuals (Fehrenbach 2017, PMID 28190087).

Evidence that standard ICS prevents or reverses all remodeling is incomplete. ICS clearly suppresses inflammation and attacks; effects on individual structural compartments vary by outcome, timing and disease duration (Venge 2010, PMID 20500605).

Type-2-low and non-type-2 states

“Type-2-low” generally means that currently measured type-2 biomarkers are not elevated. It does not identify one alternative mechanism (Hudey 2020, PMID 33160187).

Pattern Candidate drivers Major caveat
Neutrophilic Infection/colonization, smoke/pollution, IL-17 pathways, inflammasome and NET biology Sputum neutrophilia is age-, treatment- and infection-sensitive (Seys 2019, PMID 30422895)
Obesity-associated Altered mechanics, systemic metabolic inflammation, reflux/sleep apnea and steroid pharmacology Type-2-high and obesity can coexist; body size does not define an endotype
Paucigranulocytic Smooth-muscle/neural dysfunction, treated inflammation, low-intensity or spatially missed disease A negative sputum sample is not proof of absent airway inflammation (Tliba 2019, PMID 29928921)
Smoking-related/fixed obstruction Oxidative stress, mixed granulocytes, small-airway damage Asthma, COPD and overlap labels depend on history and longitudinal physiology

Neutrophils may be causal, reactive to infection or corticosteroid exposure, or markers of severity. Failed attempts to treat a broad “neutrophilic asthma” category argue for narrower molecular subdivision rather than assuming all sputum neutrophilia shares one target (Sze 2020, PMID 31309578).

Paucigranulocytic asthma may uncouple airway obstruction from measured luminal inflammation. The category is especially vulnerable to sampling error and to reclassification across repeated sputum samples (Tliba 2019, PMID 29928921).

Viruses and exacerbation biology

Respiratory viruses interact with baseline airway state rather than acting as isolated triggers. Deficient or delayed antiviral responses, epithelial damage, allergen exposure and type-2 inflammation can amplify one another.

Rhinovirus can release epithelial IL-33 and other alarmins, linking an infection trigger to type-2 amplification; IL-33 can also participate in neutrophilic/NET-associated exacerbation pathways (Jarjour 2014, PMID 25496100; Curren 2023, PMID 37506849).

This helps explain why the same virus produces a cold in one person and a severe attack in another, but mechanistic heterogeneity prevents one universal “antiviral asthma” therapy.

What biologics have taught mechanism

Successful pathway blockade is stronger causal evidence than cross-sectional biomarker association:

  • IgE blockade establishes a causal role for allergic effector activation in a selected population (Humbert 2005, PMID 15679715).
  • IL-5/IL-5R blockade establishes eosinophil-pathway importance for attacks, while incomplete symptom and FEV1 responses show eosinophils are not the whole disease (Pavord 2012, PMID 22901886; Bleecker 2016, PMID 27609408).
  • IL-4Rα blockade connects IL-4/IL-13 signaling to attacks, airflow, FeNO and mucus biology (Castro 2018, PMID 29782217).
  • TSLP blockade demonstrates therapeutic leverage above several downstream type-2 pathways and some benefit at lower biomarker levels (Menzies-Gow 2021, PMID 33979488).

CASCADE showed tezepelumab reduced airway submucosal eosinophils and AHR but did not significantly change every measured remodeling component over the trial interval, illustrating why clinical and histologic effects should not be conflated (Diver 2021, PMID 34256031).

Open questions

  • Which structural changes are reversible, and over what time scale, after near-elimination of exacerbations with biologics? (Fehrenbach 2017, PMID 28190087; Diver 2021, PMID 34256031)
  • Are persistent mucus plugs a causal treatment target or a marker of a deeper epithelial state? (Dunican 2018, PMID 29400693; Tang 2022, PMID 35104436)
  • How stable are type-2-low, neutrophilic and paucigranulocytic labels across seasons, infections and corticosteroid exposure? (Hudey 2020, PMID 33160187)
  • Which non-type-2 molecular subgroup is sufficiently coherent for a successful targeted trial?
  • Can epithelial barrier repair prevent disease rather than only suppress established inflammation? (Holgate 2007, PMID 18073119)

References

  1. Fahy JV. Type 2 inflammation in asthma—present in most, absent in many. Nat Rev Immunol. 2015;15:57-65. PMID 25534623
  2. Hudey SN, et al. Mechanisms of non-type 2 asthma. Curr Opin Immunol. 2020;66:123-128. PMID 33160187
  3. Fehrenbach H, et al. Airway remodeling in asthma: what really matters. Cell Tissue Res. 2017;367:551-569. PMID 28190087
  4. Dunican EM, et al. Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction. J Clin Invest. 2018;128:997-1009. PMID 29400693
  5. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol. 2007;120:1233-1244. PMID 18073119
  6. Hirota N, Martin JG. Mechanisms of airway remodeling. Chest. 2013;144:1026-1032. PMID 24008953
  7. Banno A, et al. Bidirectional interaction of airway epithelial remodeling and inflammation in asthma. Clin Sci. 2020;134:1063-1079. PMID 32369100
  8. Gauvreau GM, et al. Anti-alarmin approaches entering clinical trials. Curr Opin Pulm Med. 2020;26:69-76. PMID 31408015
  9. Gauvreau GM, et al. Sounding the alarmins—the role of alarmin cytokines in asthma. Allergy. 2023;78:402-417. PMID 36463491
  10. Menzies-Gow A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. 2021;384:1800-1809. PMID 33979488
  11. Kelsen SG, et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: a randomized clinical trial. J Allergy Clin Immunol. 2021. PMID 33872652
  12. Mitchell PD, O'Byrne PM. Epithelial-derived cytokines in asthma. Chest. 2017;151:1338-1344. PMID 27818325
  13. Toki S, et al. TSLP and IL-33 reciprocally promote lung protein and ILC2 receptor expression. Allergy. 2020;75:1606-1617. PMID 31975538
  14. Humbert M, et al. Benefits of omalizumab as add-on therapy in severe persistent allergic asthma: INNOVATE. Allergy. 2005;60:309-316. PMID 15679715
  15. Pavord ID, et al. Mepolizumab for severe eosinophilic asthma (DREAM). Lancet. 2012;380:651-659. PMID 22901886
  16. Bleecker ER, et al. Efficacy and safety of benralizumab for severe asthma: SIROCCO. Lancet. 2016;388:2115-2127. PMID 27609408
  17. Castro M, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378:2486-2496. PMID 29782217
  18. Woodruff PG, et al. Genome-wide profiling identifies epithelial cell genes associated with asthma and corticosteroid response. Proc Natl Acad Sci USA. 2007;104:15858-15863. PMID 17898169
  19. Choy DF, et al. Gene expression patterns of Th2 inflammation and intercellular communication in asthmatic airways. J Allergy Clin Immunol. 2011;127:549-557. PMID 21187436
  20. Peters MC, et al. Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma. J Allergy Clin Immunol. 2014;133:388-394. PMID 24075231
  21. Gans MD, Gavrilova T. Understanding the immunology of asthma: pathophysiology, biomarkers, and treatments for asthma endotypes. Med Clin North Am. 2020;104:1-14. PMID 31678040
  22. Tang M, et al. Mucus plugs persist in asthma, and changes associate with changes in airflow over time. Am J Respir Crit Care Med. 2022. PMID 35104436
  23. Holgate ST. Pathogenesis of asthma. Clin Exp Allergy. 2008;38:872-897. PMID 18498538
  24. Black JL. Asthma—more muscle cells or more muscular cells? Am J Respir Crit Care Med. 2004;169:980-981. PMID 15107302
  25. Donovan GM, et al. Quantifying airway remodelling for research or clinical purposes: how should we normalize for airway size? Respirology. 2023;28:223-225. PMID 36691759
  26. Venge P. The eosinophil and airway remodelling in asthma. Clin Respir J. 2010;4 Suppl 1:15-19. PMID 20500605
  27. Seys SF, et al. New insights in neutrophilic asthma. Curr Opin Pulm Med. 2019;25:113-120. PMID 30422895
  28. Tliba O, Panettieri RA. Paucigranulocytic asthma: uncoupling of airway obstruction from inflammation. J Allergy Clin Immunol. 2019;143:1287-1294. PMID 29928921
  29. Sze E, et al. Mechanisms and therapeutic strategies for non-T2 asthma. Allergy. 2020;75:311-325. PMID 31309578
  30. Jarjour NN, et al. Interleukin-33: a potential link between rhinovirus infections and asthma exacerbation. Am J Respir Crit Care Med. 2014. PMID 25496100
  31. Curren B, et al. IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma. Mucosal Immunol. 2023;16:671-684. PMID 37506849
  32. Diver S, et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness: CASCADE. Lancet Respir Med. 2021;9:1299-1312. PMID 34256031