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What effect does asthma treatment have on airway remodeling? Current perspectives

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Airway remodeling, or structural changes of the airway wall arising from injury and repair, plays an important role in the pathophysiology of asthma. Remodeling is characterized as structural changes involving the composition, content, and organization of many of the cellular and molecular constituents of the bronchial wall. These structural changes can include epithelial injury, subepithelial thickening/fibrosis, airway smooth muscle hyperplasia, goblet cell hypertrophy and hyperplasia, and angiogenesis. Historically, these changes are considered a consequence of long-standing airway inflammation. Recent infant and child studies, however, suggest that remodeling occurs in parallel with inflammation in asthmatic subjects. Despite advancements in the recognition of key cellular and molecular mechanisms involved in remodeling, there remains a paucity of information about which treatments or interactions are most likely to regulate these processes. Furthermore, it is unclear as to when is the best time to initiate treatments to modify remodeling, which components to target, and how best to monitor interventions on remodeling. Indeed, inhaled corticosteroids, which are generally considered to have limited influence on remodeling, have been shown to be beneficial in studies in which the dose and duration of treatment were increased and prolonged, respectively. Moreover, several studies have identified the need to identify novel asthma indices and phenotypes that correlate with remodeling and, as a consequence, might specifically respond to new therapies, such as anti-IgE, anti–IL-5, and anti–TNF-α mAbs. Our review will evaluate the development of remodeling in asthmatic subjects and the effects of treatment on these processes.

Section snippets

What are the effects of corticosteroids on airway remodeling?

Corticosteroids, either inhaled (ICSs) or systemic (oral corticosteroids), modulate acute and chronic inflammation in asthmatic subjects, particularly in those with milder disease, and have broad pharmacologic actions.14, 15 Consequently, glucocorticoids are considered the therapeutic mainstay for chronic asthma and its underlying inflammation. Indeed, as a result of the “chronic inflammation leads to remodeling” paradigm, corticosteroids have long played a central role in interventional

What is the effect of combination treatment with ICS and long-acting β2-agonists on remodeling?

Burgess et al71 found that neither ICS nor long-acting β2-agonist (LABA) monotherapy inhibited TGF-β–stimulated release of ECM proteins and cytokines in an in vitro model. However, another recent in vitro study found that combination treatment with LABAs and ICSs versus monotherapy with either ICSs or LABAs was superior in regulating excessive matrix production in human fibroblast cultures.20 Wang et al72 demonstrated decreases in MMP-9, TIMP-1, and TGF-β levels in sputum samples and decreased

What is the effect of omalizumab on remodeling?

IgE contributes to the pathophysiology of allergic diseases by attaching to mast cells and regulating its mediator release. These mediators can then initiate a cascade of inflammation involving B and T lymphocytes, eosinophils, fibroblasts, ASM, and epithelial cells, which then results in the release of a multitude of cytokines and chemokines to intensify airway inflammation, symptoms, and possibly remodeling.75

Omalizumab is a recombinant humanized IgG1 mAb that binds to the Fc portion of free

What is the effect of mepolizumab (anti–IL-5) on remodeling?

Eosinophils play a role in airway remodeling in asthmatic subjects.30, 31 RBM thickening has been associated with increased numbers of eosinophils in the bronchial mucosa.30 Eosinophils also produce several mediators and cytokines (ie, TGF-β, VEGF, MMP-9, TIMP-1, and IL-13) that are capable of stimulating matrix remodeling.79 Interestingly, eosinophil-deficient mice are protected from peribronchiolar collagen deposition and increases in ASM; however, increases in AHR and mucus secretion still

What are the effects of anti–TNF-α on remodeling?

There is limited evidence that therapies against TNF-α are effective in subjects with severe asthma. However, in addition to promoting airway inflammation and AHR, TNF-α might play a central role in airway remodeling and induce glucocorticoid resistance, myocyte proliferation, vascular remodeling, and stimulation of fibroblast growth and maturation into myofibroblasts by promoting TGF-β expression.84, 85 Patients with treatment-refractory asthma have an upregulation of their TNF-α axis.86

What effects do leukotriene modifiers, anticholinergics, and tyrosine kinase inhibitors have on remodeling?

Although an extensive discussion of all treatments is beyond the scope of this article, to be more inclusive, it is helpful to briefly highlight the role of leukotriene modifiers, anticholinergics, and tyrosine kinase inhibitors in airway remodeling. Most of these observations lack human studies for confirmation.

Leukotriene modifiers suppress eosinophilic infiltration and eosinophil numbers in peripheral blood, sputum, and bronchoalveolar lavage fluid samples, as well as improving AHR and lung

Conclusions

Airway remodeling is a complex and incompletely defined process in asthmatic subjects that might contribute to pathophysiology, progression of airflow obstruction, and ultimately treatment responsiveness. Understanding which components of remodeling contribute to various physiologic consequences of asthma remains an important tenet of future pathophysiological, diagnostic, and therapeutic approaches. Additionally, there must be human studies to assess the effects of higher dosing and longer

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