Effect of asthma medication on airway remodeling
Bronchial asthma (asthma) is an inflammatory airway disease with reversible airflow limitation, but as the disease progresses and airway inflammation advances, airway remodeling occurs in most patients. Airway remodeling can lead to irreversible airflow limitation, making asthma symptoms difficult to control. A recent study found that airway inflammation occurs in parallel with remodeling [1], meaning that airway remodeling is present in the early stages of asthma, which highlights the importance of inhibiting airway remodeling in the control of asthma. In this paper, we present a review of the effects of drugs used clinically in the treatment of asthma in recent years, including glucocorticoids, long-acting β-2 agonists (LABA), leukotriene modulators, anti-Ig-E monoclonal antibodies, anti-IL-5 monoclonal antibodies, and tyrosine kinase inhibitors, on the process of airway remodeling, in order to gain a more comprehensive understanding of the effects of pharmacotherapy on airway remodeling and its mechanisms of action, and thus contribute to the optimization of The effects of glucocorticoid therapy on airway remodeling
I. Effect of glucocorticoid therapy on airway remodeling
Glucocorticoid (GC) is the first-line anti-inflammatory drug for the treatment of asthma, and some studies have found that after asthma patients have reached control level by inhaled glucocorticoid (ICS) treatment, continuing low-dose ICS can slow down the development of airway remodeling and reduce the degree of airway remodeling. The effects of GC on airway remodeling are discussed below in terms of the mechanisms of airway remodeling.
1 , Inhibition of reticular basement membrane thickening
An important feature of airway remodeling is subepithelial fibrosis and thickening of the reticular basement membrane (RBM). RBM thickening is present in patients with varying degrees of asthma and is directly associated with airway obstruction and airway hyperresponsiveness (AHR) [2]. It is mainly caused by an imbalance of matrix synthesis and breakdown due to increased expression of TGF-β, matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP), as well as collagen deposition.
Back in the 1990s Sont et al. designed a randomized controlled prospective study to observe changes in basal RBM thickness as well as in RBM thickness after 2 years by giving ICS treatment to 75 patients with mild-moderate asthma. At the baseline level, there was no significant difference in RBM thickness between the ICS-treated and control groups. After 2 years of treatment, RBM thickening was significantly reduced and FEV1 increased in the ICS-treated group compared with the control group, and the incidence of asthma exacerbations was 1.8-fold lower in the ICS-treated group compared with the control group, confirming that ICS treatment could control the development of airway remodeling by inhibiting RBM thickening [3]. Later, Wart et al. examined bronchial RBM thickness, lung function indices, airway inflammation, and AHR in asthmatic patients before and after inhalation of high-dose fluticasone propionate in a randomized, double-blind, placebo-controlled parallel trial. wheezing symptoms, lung function, and airway inflammation were significantly improved in the fluticasone group after 3 months of treatment, but no changes in RBM thickness or AHR were found. A decrease in RBM thickness and an increase in FEV1 in the fluticasone treatment group were found only after 12 months of treatment. It was further confirmed that long-term use of ICS inhibited RBM thickening [4].
Studies by Sont, Ward et al. have confirmed that long-term use of ICS attenuates asthma airway remodeling by inhibiting RBM thickening, which is contrary to the GINA guidelines that state that the dose of ICS should be gradually reduced according to the improvement of lung function and symptoms leading to discontinuation. If the treatment is based on the guideline protocol, some patients may lose the opportunity to reverse airway remodeling and AHR by stopping ICS prematurely, which is really worth our consideration.
2 .Inhibition of airway smooth muscle proliferation
The increase of Airway smooth muscle ASM cells and fibroblasts in the proximal bronchus is also one of the important features of airway remodeling. Glucocorticoids can inhibit the proliferation of ASM either directly by acting on these cells or indirectly by modulating cytokines, among other parts [5]. Biopsies of rats with chronic asthma given long-term ICS treatment revealed a significant reduction in bronchial ASM thickness compared to controls [6].By performing allergen excitation in 14 asthmatic patients and performing fiberoptic bronchoscopy 24 hours later, Kelly et al. found that the area of ASM in the airways of patients given budesonide treatment was reduced compared to controls, but the allergen-induced increase in fibroblasts was not improved. Therefore, it was inferred that airway smooth muscle cells may have differentiated into fibroblasts and transferred to the submucosa, resulting in the increase of fibroblasts and the decrease of ASM area. Although budesonide reduced the ASM area, it did not inhibit the increase of fibroblasts. However, budesonide combined with formoterol inhalation therapy significantly reduced the number of airway fibroblasts and inhibited the reduction of ASM area, suggesting that the combined therapy has better anti-inflammatory and anti airway remodeling effect than ICS alone [7].
3 , Reduction of bronchial epithelial cell injury and separation
Epithelial cell damage is one of the features of airway inflammation and remodeling in asthmatic patients. Epithelial cells are located at the primary location of airway defense, and their structural disruption and functional impairment are at the origin of airway inflammation and remodeling in asthma.
There are different perspectives on the role of glucocorticoids on bronchial epithelial damage. In vitro culture of epithelial cells revealed that glucocorticoids induced apoptosis of epithelial cells and prolonged the repair process of epithelial damage, suggesting an inhibitory effect of hormones on the repair of epithelial damage [8]. However, by observing the naked epithelial cells in the airways of guinea pigs, it was found that the repair process of epithelial cells could still occur when glucocorticoids were given by inhalation, and therefore it was concluded that hormones did not affect the self-repair process of epithelial cell damage [9]. Clinical trials further found that the number of epithelial cells in sputum specimens from asthmatic patients treated with budesonide inhalation increased significantly, suggesting that ICS treatment is beneficial for the repair of airway epithelial damage [10].
4 , Inhibition of cupulocytosis/mucus hypersecretion
The role of cupulocytosis and mucus hypersecretion in asthma is unclear. The presence of these alterations has not been confirmed in the airways of patients with mild-moderate asthma, but the large number of mucus plugs found in the airways of some patients with severe asthma suggests the possible presence of cupulocytosis and mucus hypersecretion [11]. Excessive mucus production and secretion can block the airways, impairing lung function and causing obstructive ventilatory dysfunction. There are few studies on the number and function of therapeutic cupped cells, and De Kluijver et al. found a reduction in the number of cupped cells in the airways of asthmatic patients after 2 weeks of low-dose inhalation of budesonide compared to blank controls [12]. In addition, ICS inhalation was also observed to reduce the extent of airway cupped cell chemosis in a rat model of chronic asthma, suggesting that ICS inhalation treatment may have an inhibitory effect on cupped cell chemosis and mucus hypersecretion [6].
5 , Inhibition of vascular remodeling
Vascular remodeling in asthmatics is mainly caused by angiogenesis stimulated by vascular endothelial growth factor. ICS can affect vascular remodeling through a number of mechanisms, including vasoconstriction, inhibition of chronic airway inflammation, inhibition of the production of pre-angiogenic cytokines/inflammatory chemokines (IL-8, GM-CSF, etc.), inhibition of the function of immune cells expressing pre-angiogenic cytokine immune cell function (e.g., basophils, eosinophils, macrophages), and reduced VEGF expression [13].Chetta et al. found that the dose of ICS was negatively correlated with airway blood supply after inhalation of different doses of ICS in asthmatic patients, such that inhalation of high doses of beclomethasone propionate or fluticasone propionate significantly reduced vascular-related remodeling [14]. Feltis et al. also found a reduction in both subepithelial vascularity and VEGF expression by bronchoscopy after 3 months of treatment with fluticasone propionate (1500 mg inhaled daily) given to asthma patients on first-time hormone use [15]. It is suggested that ICS treatment can inhibit vascular remodeling in asthma, thus slowing down the progression of airway remodeling.
II. Effect of ICS combined with LABA treatment on airway remodeling
It was found that the combination of LABA and ICS treatment was more effective in inhibiting fibroblast production of extracellular matrix compared with monotherapy [16]. Wang Ke et al. found that the expression levels of MMP-9, TIMP-1, and TGF-β in sputum specimens from asthmatic patients treated with ICS combined with LABA decreased significantly compared with the ICS-treated group, and the airway wall thickness was also relatively reduced, demonstrating that combination therapy is more advantageous in inhibiting airway remodeling [17].
A 52-week parallel, controlled, randomized, double-blind clinical study was conducted through 17 patients with asthma treated with budesonide/formoterol (200/6 mg, twice daily) and budesonide/formoterol (800/12 mg, twice daily), respectively, and found a significant reduction in airway RBM thickness in both different dose treatment groups after 52 weeks, and the difference between the two groups was not significant [18]. It is suggested that the dose of ICS and LABA is not a factor affecting airway remodeling, and small doses of ICS inhalation are rather more advantageous because of the reduced side effects, therefore, long-term small doses of inhaled ICS and LABA are advocated to control the occurrence and development of airway remodeling.
The effects of leukotriene modulators and anticholinergic drugs on airway remodeling
Leukotriene modulators can inhibit eosinophil infiltration in peripheral blood, sputum and BALF samples. Eosinophils, in turn, play an important role in airway remodeling in asthmatic patients by producing various inflammatory mediators and cytokines (e.g., TGF-β, VEGF, MMP-9, TIMP-1, IL-13) that lead to stromal hyperplasia and RBM thickening [19].Henderson et al. found that airway eosinophil infiltration by giving montelukast treatment to asthmatic mice and cupulocytosis were significantly reduced and partially reversed the pre-existing increase in airway ASM and subepithelial collagen deposition, confirming the anti-airway remodeling effect of montelukast [20].Muz et al. obtained similar results in a repeat test and found a significant reduction in airway epithelial peeling in mice in the montelukast-treated group compared to the control group [21], suggesting that montelukast treatment inhibits airway epithelial damage and also may be one of the mechanisms of anti-airway remodeling.
Acetylcholine promotes airway remodeling by increasing ASM contractile protein expression, pro-mitotic cell proliferation, and releasing inflammatory mediators. The effects of anticholinergic drugs, such as ipratropium bromide and tiotropium bromide, which are widely used clinically, on bronchodilatation have been confirmed in the treatment of COPD and asthma, but their effects on airway remodeling have not been confirmed.Bos et al. found through a guinea pig asthma model that tiotropium bromide treatment completely inhibited bronchial mucus gland hypertrophy and partially inhibited ASM thickening, contractile protein expression, airway proliferation of eosinophils and cupped cells, suggesting an inhibitory effect on airway remodeling [22]. Similar results were confirmed in a replicated trial in a mouse model and further revealed that tiotropium alleviated AHR by reducing the expression of Th2 cytokines (e.g., TNF-β) [23]. However, further confirmation is needed in additional, prospective clinical trials.
IV. Effect of anti-IgE monoclonal antibodies on remodeling
IgE binds to mast cells and regulates mast cell degranulation resulting in a type I metaplasia. Subsequent activation of B and T cells, basophils, fibroblasts, ASM and epithelial cells, etc., releases a variety of cytokines and inflammatory mediators that exacerbate airway inflammation and remodeling. Omalizumab, a humanized IgG1 monoclonal antibody (IgG1 mAb), binds to the Fc fragment of circulating free IgE, blocks its binding to mast cells, basophils, and dendritic cells, reduces circulating levels of IgE, and downregulates IgE receptor expression, thereby inhibiting the metaplastic response [24].
There are many studies on the inhibition of airway inflammatory response by omalizumab, but few studies on the effect on airway remodeling.Huang et al. found in vitro in cultured bronchial epithelial cells that omalizumab treatment significantly reduced the production of preinflammatory cytokines and growth factors (e.g., TNF-α , TGF-β), thereby inhibiting the airway remodeling process [25]. In addition, Zietkowski et al. found a significant reduction in the level of vascular endothelial constrictor in exhaled breath condensate after 1 year of omalizumab treatment in patients with severe persistent asthma [24]. Vascular endothelial constrictor is a growth factor secreted by fibroblasts and plays a role in promoting vascular and airway remodeling.
V. Effect of anti-IL-5 monoclonal antibody on airway remodeling
Flood-Page et al. found that treatment of asthma patients with anti-IL-5 monoclonal antibody (mepolizumab) reduced eosinophils in airway tissue by about 50% and the expression of tendon glycoproteins, basement membrane glycans, and precollagen III in the bronchial RBM, suggesting that anti-IL-5 monoclonal antibody has an important role in the treatment of asthma. , and procollagen III expression, suggesting an inhibitory effect on airway remodeling, but no changes in lung function were found [26]. Another randomized, placebo-controlled parallel trial, in which a suitable patient population was selected by high criteria (recurrent wheezing episodes despite administration of high-dose glucocorticoids, presence of persistent airway eosinophil infiltration, and sputum eosinophil fraction greater than 3%), found that administration of mepolizumab significantly reduced the frequency of acute asthma exacerbations, as well as sputum and BALF eosinophil The frequency of acute asthma exacerbations and the number of eosinophils in sputum and BALF were significantly reduced after mepolizumab treatment, and the airway wall area and total airway area were significantly increased [27], suggesting that mepolizumab treatment helps improve lung function. In addition, Nair et al. found a mild increase in FEV1 after mepolizumab treatment [28].
In addition, the role of tyrosine protease inhibitors (e.g., erlotinib, imatinib) in oncology treatment has been demonstrated, but the role in asthma treatment is unclear.Kung et al. administered erlotinib treatment in ovalbumin-sensitized Norwegian rats and found reduced collagen deposition and ASM thickness around the airways, reduced peribronchial angiogenesis, and reduced Th2 cytokines (including IL-4, IL -5, IL-10, IL-13, TNF-α, TGF-β) were significantly reduced and improved AHR, suggesting that erlotinib has an inhibitory effect on airway remodeling [29]. However, there are few relevant studies, and more studies are needed to further explore this.
In summary, the onset and development of airway remodeling can ultimately result in incomplete reversible airflow limitation in asthma patients, which can make asthma symptoms difficult to control. Throughout the current drugs used to treat asthma, such as glucocorticoids, LABA and leukotriene modulators can inhibit the occurrence and development of airway remodeling by inhibiting the thickening of RBM, the proliferation of ASM and the expression of inflammatory factors, reducing the level of circulating IgE, as well as reducing the number of eosinophils and inhibiting their functions, thus facilitating the early prevention and treatment of airway remodeling in asthma patients, and ultimately can optimize the treatment of asthma.