Abstract

Asthma is a chronic disease of the airways that has long been viewed predominately as an inflammatory condition. Accordingly, current therapeutic interventions focus primarily on resolving inflammation. However, the mainstay of asthma therapy neither fully improves lung function nor prevents disease exacerbations, suggesting involvement of other factors. An emerging concept now holds that airway remodeling, another major pathological feature of asthma, is as important as inflammation in asthma pathogenesis. Structural changes associated with asthma include disrupted epithelial integrity, subepithelial fibrosis, goblet cell hyperplasia/metaplasia, smooth muscle hypertrophy/hyperplasia, and enhanced vascularity. These alterations are hypothesized to contribute to airway hyperresponsiveness, airway obstruction, airflow limitation, and progressive decline of lung function in asthmatic individuals. Consequently, targeting inflammation alone does not suffice to provide optimal clinical benefits. Here we review asthmatic airway remodeling, focusing on airway epithelium, which is critical to maintaining a healthy respiratory system, and is the primary defense against inhaled irritants. In asthma, airway epithelium is both a mediator and target of inflammation, manifesting remodeling and resulting obstruction among its downstream effects. We also highlight the potential benefits of therapeutically targeting airway structural alterations. Since pathological tissue remodeling is likewise observed in other injury- and inflammation-prone tissues and organs, our discussion may have implications beyond asthma and lung disease.

Background

Asthma is defined as ‘a heterogeneous disease, usually characterized by chronic airway inflammation… (and) by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and cough that vary over time and in intensity, together with variable expiratory airflow limitation’ by the Global Initiative for Asthma [1]. Pathologically, key features of asthma include chronic inflammation along with airway tissue remodeling, encompassing disrupted epithelial integrity [2,3], a thickened subepithelial layer [4], subepithelial fibrosis [5,6], goblet cell hyperplasia [7,8], smooth muscle hypertrophy/hyperplasia [7], enhanced vascularity [9], and increased collagen deposition [7]. Such changes occur in large and small airways [10]. Consistently, high-resolution computed tomography (CT) images of individuals with asthma of varying severity show extensive tissue abnormalities indicative of airway remodeling [11,12].

These structural changes are hypothesized to result in airway hyperresponsiveness (AHR), airway obstruction, airflow limitation [13–17], and progressive decline of patients’ lung function [18]. Airway remodeling also correlates with disease severity [4,10,19]. Severe asthmatics show thicker airway walls [20,21], narrower airway lumen [21,22], and focal bronchial stenoses [21] compared with controls as assessed by quantitative CT analyses. Another CT analysis also associated gas trapping, indicative of small airway obstruction [23], with a history of asthma-related hospitalizations, ICU visits, and mechanical ventilation [24]. Moreover, airway remodeling has been implicated as the source of steroid resistance in asthmatic patients [25,26]. Thus, while asthma has long been considered a disease of chronic inflammation, evidence suggests that structural alterations contribute equally to disease development and exacerbations [2,26–28].

An evolving hypothesis proposes that rather than sequential or consequential, airway inflammation and remodeling are concurrent, interdependent events that promote and sustain each other. Accordingly, failure to account for airway remodeling translates to incomplete therapeutic strategies for asthma. The American Thoracic Society recognizes airway remodeling as a central aspect of asthma, and has published a statement calling for further research to understand the pathology and mechanisms of airway remodeling, and expedited development of therapeutics to target it [29]. This review thus explores this alternative view of asthma pathogenesis, including the role of airway remodeling, its relationships with airway inflammation, and therapeutic implications. Deeper understanding of airway remodeling may break new ground for how we approach asthma treatment.

Airway remodeling and resulting pulmonary dysfunction arise from aberrance in different cell types and their interactions. Myofibroblasts are key contributors to subepithelial thickening/fibrosis and enhanced collagen deposition as prominent sources of extracellular matrices (ECMs), primarily collagen [6]. Circulating fibrocytes can also contribute, by migrating into the lungs and differentiating into myofibroblasts [30,31]. Hyperplasia of goblet cells leading to excessive mucus production and secretion is linked to airway occlusion [2]. Hypertrophy/hyperplasia of airway smooth muscle cells increases airway smooth muscle mass and causes airway obstruction [28]. New blood vessels generated during asthma-induced angiogenesis can be hyperpermeable, causing airway edema [2], and increased vascularity contributes to thickened airway walls [2]. Based on available evidence that epithelial modifications are central to airway remodeling and asthma pathogenesis [28,32], this review focuses on airway epithelium and its interactions with underlying mesenchyme.

Airway epithelium as a first line of defense

Airway epithelium consists mostly of ciliated columnar epithelial cells, mucus-secreting goblet cells, surfactant-secreting club cells, and pluripotent basal cells [33–35]. Basal cells are thought to give rise to ciliated and secretory epithelial cells during growth and regeneration [33,34,36]. Assisted by tight junctions, adherens junctions, and desmosomes that allow intercellular communication, these resident epithelial cells form a cohesive layer and inhibit infiltration of damaging substances from the lumen into underlying tissues [34,35,37]. The physical barrier is further fortified by a layer of mucus with antimicrobial, antiprotease, and antioxidant properties [35,38]. Inhaled particles and pathogens trapped in mucus are cleared from the respiratory tract by ciliated columnar cells [35,39].

Airway epithelium provides physical and chemical defenses and immunological barrier. A critical part of its function is to determine when maximal immune responses are needed. In the presence of innocuous antigens, airway epithelial cells (AECs) restrain immune reactions by suppressing activation and functions of pro-inflammatory mediators [35], while also restricting their own sensitivity and reactivity [35]. Toll-like receptors (TLRs) are key pattern recognition receptors on AECs, that are actively maintained in a hyporeactive state [35]. Physical and chemical barrier functions of airway epithelium limit antigens’ access to the cells of the immune system, preventing inappropriately strong immune responses [34,35]. AECs also block exaggerated inflammatory responses by secreting anti-inflammatory factors [40]. Allergen challenge or tissue damage activates TLRs, which initiate signaling pathways that lead to secretion of pro-inflammatory cytokines [35,39]. The multifunctional airway epithelium directly and indirectly maintains a healthy respiratory tract and protects underlying tissues against harm by inhaled substances [33,34,37,41]. In contrast, a compromised airway epithelium poses a major threat to the respiratory system [42]. Disruption in physical barriers via broken intracellular junctions and weakened chemical defense can increase permeability to harmful substances and failure to neutralize them, allowing damage to structures and cellular proteins, lipids, and DNA of underlying tissues. Impaired immunological defense combined with increased penetration by allergens causes sensitization and inappropriate activation, leading to exaggerated immune responses such as seen in asthma.

Epithelial–mesenchymal communication

During fetal lung development and pulmonary wound repair, homeostasis of the airway microenvironment is maintained through communication between the airway epithelium and the mesenchyme via various soluble factors, via a system termed as the epithelial–mesenchymal trophic unit (EMTU) [43–46]. The similarity of airway remodeling in asthma to that of fetal morphogenesis gave rise to the concept that the EMTU remains active postnatally in some individuals or becomes reactivated during asthma pathogenesis [44,47,48]. This EMTU model of asthma posits that repeated environmental insults promote dysregulation of epithelial–mesenchymal cross-talk, causing amplified inflammatory responses, aberrant airway remodeling, and incomplete tissue repair [47,49], thereby enabling defective remodeling signals to migrate further into the underlying tissues [48].

The concept of inappropriate tissue repair/restoration in asthma is supported by findings of Plopper et al. [47] that showed that repeated allergen exposure reactivates EMTU and induces structural changes in the airways of infant rhesus monkeys. In vitro studies revealed that stressed AECs can initiate a fibroblast response that promotes proper repair [50,51]. In asthmatic individuals, this stress response is exaggerated, evidenced by increased pro-fibrogenic transforming growth factor-β (TGF-β) signaling [52,53]. Its ability to promote differentiation of fibroblasts to myofibroblasts [54,55] and enhance survival of lung myofibroblasts [56] makes heightened TGF-β signaling relevant to asthma-associated airway remodeling. Analyses of biopsy samples support these in vitro findings, as myofibroblasts were more numerous in asthmatic patients than in controls, and proportional in number to subepithelial collagen thickness [57]. Also, fibroblasts isolated from bronchial biopsies of asthmatic patients were found more responsive to TGF-β1 than those of normal controls [58]. Myofibroblasts also release the mitogens endothelin-1 and vascular endothelial growth factor (VEGF) [59], which can stimulate proliferation of smooth muscle and endothelial cells [59]. Thus, via mediators such as TGF-β, an impaired epithelium conveys altered signals to mesenchymal and other surrounding tissues in the airways.

Epithelial–mesenchymal transition

Supporting the role of abnormal airway epithelium in asthma pathogenesis is the concept that AECs undergo molecular reprogramming, known as epithelial–mesenchymal transition (EMT), and transform into resident fibroblasts [60]. This pathological transdifferentiation is hypothesized to contribute to fibroblast accumulation and activation seen in the thickened subepithelial layer of patients with asthma, and also substantiates the resemblance of fetal lung morphogenesis to asthma pathogenesis. During physiological EMT, cells lose their epithelial features, such as cell polarity and intercellular adhesion, and acquire migratory and invasive properties associated with mesenchymal cells. Such mobility gains would enable transformed cells to translocate into airway submucosa, as supported by findings of such AEC plasticity [60–62]. Samples from asthmatic individuals showed more robust responses to the EMT inducer TGF-β than those of healthy controls, seen in greater numbers of TGF-β-responsive basal cells and reduced epithelial and enhanced mesenchymal cell markers [60]. Also implying that EMT is dysregulated in asthma are increased [63,64] but dyssynchronous cell proliferation [65] and resulting impairment in wound healing ability [63,65] of asthmatic epithelial cells. Consistent with these in vitro findings, chronic aeroallergen exposure in mice caused thickening of the airway smooth muscle layer, along with decreased E-cadherin and increased vimentin expression in lungs [61]— characteristic features of an activated EMT program. Cells of airway epithelial origin were also found to have migrated into the subepithelial layer and into smooth muscle. Also, these transformed cells expressed pro-collagen, supporting EMT’s contribution to subepithelial thickening and enhanced collagen deposition in asthma. Further substantiating these in vivo and in vitro findings, an unbiased gene network analysis of eight independent asthma gene expression microarray datasets revealed shared suppression of epithelial differentiation programs across mild, moderate, and severe asthma, and identified core signature genes pointing to induction of mesenchymal proliferation and dysregulation of epithelial–mesenchymal signaling. These findings underscore the loss of epithelial integrity and homeostasis in asthma [62].

These data introduce the notion that in asthma, aberrant cell differentiation may debilitate the injured epithelium’s ability to regenerate and restore its function as a barrier against environmental insults, apart from contributing to enhanced subepithelial mass and density. In fact, multiple lines of evidence associate disrupted tight junctions, increased epithelial permeability, and injury susceptibility with asthma [33,49,66–68]. Thus, structural and functional impairments of airway epithelium are major risk factors for asthma, which sensitize the host to repeated environmental insults and potentiate defective tissue repair and remodeling, while also dysregulating inflammatory responses [6,69].

Metalloproteolytic equilibrium of the airway microenvironment

In addition to growth factors and cytokines, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) also act as key mediators of epithelial–mesenchymal communication during airway remodeling. A balance between MMPs and TIMPs secreted by epithelium and mesenchyme is crucial in maintaining appropriate ECM turnover, and deviations in levels of these enzymes can potentially perturb homeostasis of the microenvironment, as in asthmatic airways. Accordingly, levels of the airway remodeling-associated proteinase MMP-9 and proteinase inhibitor TIMP-1 seen in asthmatic patients were significantly higher than in healthy controls [70–72]. Levels of the latent form of MMP-2, another potent collagenase, were likewise elevated in individuals with asthma compared with controls [72], but those of its active form in asthma patients with the disease have not been assessed. In addition to their effects upon ECM, MMPs may contribute to smooth muscle hypertrophy/hyperplasia, a prominent feature of airway remodeling, via autocrine promotion of smooth muscle cell proliferation [73]. MMP-2 secreted by primary human bronchial epithelial cells was found to stimulate mitogenesis in primary fibroblasts [74], which could promote subepithelial fibrosis. This finding underscores the multifaceted impact of dysfunctional communication between the epithelial and mesenchymal compartments during asthma development.

Many studies agree on enhanced MMP and TIMP-1 levels, but data on MMP-9:TIMP-1 ratios remain inconclusive. Some studies found decreased MMP-9:TIMP-1 ratios in individuals with untreated asthma [70,71], an imbalance predicted to foster an anti-proteolytic microenvironment that promotes collagen accumulation. In contrast, others reported increased MMP-9:TIMP-1 ratios [75,76], suggestive of a proteolytic microenvironment contrasting with the enhanced ECM deposition actually seen in asthmatic airways. Nevertheless, the appropriate equilibrium between pro- and anti-proteolytic factors probably varies at different stages of physiological tissue repair and restoration. For example, excessive ECM degradation due to enhanced MMP activity at a given point during repair may be followed by an anabolic healing stage that elicits increased ECM synthesis. Also, MMPs and their inhibitors regulate pro-inflammatory cytokines and growth factors that require proteolytic cleavage to become activated. Thus, inflammation ongoing at time of sampling might affect interpretation of findings. Likewise, because MMPs and TIMP-1 are produced by multiple cell types including cells of the immune system, their concentrations may vary based on the numbers and types of inflammatory cells within samples. Also, because asthma encompasses multiple distinct phenotypes [77], the levels and ratios of MMPs and TIMP-1 may be phenotype-specific. In summary, imbalance of MMP and TIMP levels likely contributes to altered airway microenvironments in asthma, but further studies are still needed for clarification.

Airway remodeling

Inflammation is a physiologically valuable process that allows tissues to eliminate harmful agents, when not excessive [45]. When acute inflammation causes airway or lung injury, the epithelium undergoes repair and regenerative processes to restore homeostasis [6,78]. Because in asthma the airway epithelium is damaged and healing impaired, the lung remains compromised. Incomplete wound healing then leads to the chronic, uncontrolled inflammation seen during asthma pathogenesis. Such chronic inflammation is thought to be the primary cause of asthma-associated airway remodeling [6,78].

Amplified immune responses in asthma are often of type 2 immunity driven by T helper 2 (Th2) effector and type 2 innate lymphoid cells [79], although eosinophils, mast cells, neutrophils, macrophages, and dendritic cells also infiltrate asthmatic airways and collectively support exaggerated airway inflammation [2]. Bronchoalveolar lavage (BAL) fluid of asthmatic individuals exhibited elevated levels of transcripts encoding key Th2 cytokines such as interleukin (IL)-4 and IL-5 [80,81]. Also, antigen challenge induced IL-13 expression in BAL cells from patients with asthma, but not those from controls [81]. Overexpression of these Th2 cytokines in mice promotes asthma-associated structural modifications. For example, lung-specific IL-5 overexpression in mice led to goblet cell hyperplasia, epithelial hypertrophy, increased collagen deposition, and airway eosinophilia [82]. IL-4 overexpression also caused hypertrophy of PAS-positive epithelial cells, suggestive of goblet cell metaplasia/hypertrophy, as well as eosinophilia and enhanced collagen deposition [83,84]. Likewise, airway-targeted expression of IL-13 resulted in increased subepithelial collagen, goblet cell hyperplasia with mucus hypersecretion, and eosinophilia [85]. Among the key cytokines involved in asthma pathogenesis, IL-13 contributes to multiple signaling pathways that execute inflammatory responses and tissue remodeling [86,87]. For example, IL-9 depends on IL-13 for its effects on airway remodeling in mice [88–90], and IL-13 induces airway remodeling by promoting TGF-β signaling in vivo and in vitro [91,92]. A downstream effector of IL-13, STAT-6, helps mediate elevated mucin expression and mucus production and promotes subepithelial fibrosis in mice [93]. These findings corroborate the concept that mediators of Th2-associated immune responses are critical drivers of asthma-related airway remodeling.

Despite the roles of inflammatory mediators in asthma, corticosteroids (CSs) aimed at alleviating inflammation neither completely normalize lung function nor prevent disease exacerbations [94]. In mice, airway dysfunction reportedly persisted even after inflammation was resolved [95]. Also, the precise inciting factor of asthmatic individuals’ allergic reactions often remains unidentified [6]. Epidemiological analyses have also failed to establish a strong association between atopy and asthma [96]. These findings challenge the long-held notion that exaggerated inflammatory response alone mediates asthma pathogenesis.

A more recent hypothesis thus proposes that airway remodeling occurs independently, in parallel with chronic inflammation during asthma pathogenesis. Characteristic features of airway remodeling were equally present in biopsy samples from individuals with allergic and non-allergic asthma [97]. Also, changes in airway structure and properties can be detected at an early stage of asthma in children, even before they are diagnosed, or when still asymptomatic [98–101]. Also in pediatric patients, Pohunek et al. found no correlation between subepithelial collagen thickness and age or duration of asthma symptoms [101]. Increased susceptibility to asthma has been linked to factors that affect structure and function of developing lungs, such as prenatal/postnatal tobacco exposure [78] and childhood viral infections [32]. Taken together, these findings support the early occurrence of airway remodeling and its direct relation to asthma development, and the idea that airway structural modifications are not simply consequences of chronic inflammation. In line with this concept, goblet cell hyperplasia preceded infiltration of eosinophils and lymphocytes, and persisted after their clearance in a murine model of allergic asthma [102]. The observed correlation of airway remodeling with disease severity [4,10,19] implies that it progresses alongside the disease. Underscoring that asthma is not solely driven by inflammation, available evidence supports the idea that eliminating inflammation might not interdict progression of airway remodeling, and thereby improve lung function or disease progression.

Interdependence of inflammation and remodeling

Definitive demonstration that airway remodeling can occur without inflammation during asthma pathogenesis will be challenging. However, a plausible hypothesis is that the relationships between these elements of asthma-related pathology are bidirectional: just as inflammation contributes to airway remodeling, structural changes can influence inflammatory responses. Indeed, abnormal airway remodeling supports sustained inflammation and further remodeling, by creating a new microenvironment populated by an atypical repertoire of cells and molecules. Both human and experimental data show that AECs and other airway resident cells can be induced to secrete various cytokines, chemokines, and growth factors that facilitate infiltration, activation, differentiation, and survival of inflammatory cells [103–112]. In vitro, an engineered asthmatic epithelium, but not its normal counterpart, induced preferential differentiation of IL-5-producing lymphocytes [113]. ECM proteins can also promote inflammation. For example, proteoglycans that are major ECM constituents bind IL-5 [114] or co-localize with TGF-β1 [115], suggesting ability to store cytokines and growth factors. Furthermore, MMPs that show enhanced expression and activities in asthma can cleave and release cytokines and growth factors from ECM, fueling proliferation of resident and inflammatory cells [116]. Adhesion to fibronectin can stimulate basophils and eosinophils, promoting their release of mediators and survival [117–119]. Thus, airway inflammation and remodeling sustain each other during disease development (Figure 1). Such interdependence is likely instrumental in perpetuating the clinical symptoms of asthma. Accordingly, therapeutically targeting one of these features but not the other would fail to deliver adequate clinical improvement.

Airway remodeling and chronic inflammation in asthma

Figure 1
Airway remodeling and chronic inflammation in asthma

Exposure of the normal, healthy airway epithelium (left) to inhaled irritants is associated with various structural changes in the tissue: e.g., mucus hypersecretion, disrupted epithelial integrity, goblet cell hyperplasia/metaplasia, a thicker subepithelial layer, subepithelial fibrosis featuring (myo)fibroblasts, and smooth muscle hypertrophy/hyperplasia. An increase in collagen deposition and an imbalance in MMP and TIMP levels are also observed. Via secretion of various molecules (e.g., GM-CSF, SCF, TSLP, TGF-β), this altered airway epithelium provides a microenvironment that promotes infiltration, activation, differentiation, and survival of inflammatory cells. In turn, pro-inflammatory agents (e.g., IL-4, IL-5, and IL-13) secreted by mediators of Th2-associated immune responses re-activate EMTU, stimulate TGF-β signaling, and aggravate tissue damage, sustaining the airway remodeling. Thus, airway inflammation and remodeling maintain each other during asthma pathogenesis. Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; SCF, stem cell factor; TSLP, thymic stromal lymphopoietin.

Figure 1
Airway remodeling and chronic inflammation in asthma

Exposure of the normal, healthy airway epithelium (left) to inhaled irritants is associated with various structural changes in the tissue: e.g., mucus hypersecretion, disrupted epithelial integrity, goblet cell hyperplasia/metaplasia, a thicker subepithelial layer, subepithelial fibrosis featuring (myo)fibroblasts, and smooth muscle hypertrophy/hyperplasia. An increase in collagen deposition and an imbalance in MMP and TIMP levels are also observed. Via secretion of various molecules (e.g., GM-CSF, SCF, TSLP, TGF-β), this altered airway epithelium provides a microenvironment that promotes infiltration, activation, differentiation, and survival of inflammatory cells. In turn, pro-inflammatory agents (e.g., IL-4, IL-5, and IL-13) secreted by mediators of Th2-associated immune responses re-activate EMTU, stimulate TGF-β signaling, and aggravate tissue damage, sustaining the airway remodeling. Thus, airway inflammation and remodeling maintain each other during asthma pathogenesis. Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; SCF, stem cell factor; TSLP, thymic stromal lymphopoietin.

Therapeutic implications of airway remodeling

Understanding is incomplete of how different elements of airway remodeling, alone or in combination, affect lung function [120,121]. This knowledge gap partly reflects a lack of clinical readouts that can be used to assess airway remodeling precisely, along with the technical difficulty of using endobronchial biopsy to sample along the entire airway wall for analysis [121]. In addition to such scarcity of clinical data on airway remodeling in asthma, available preclinical data are often inconclusive. Nevertheless, structural changes have been found associated with pathological features of asthma such as AHR [16,17], airway narrowing [16,17], and airway obstruction [122], suggesting that reversing such changes may benefit those with asthma. Because asthma has long been considered a disease of chronic inflammation, the primary objective of current therapies is to control exaggerated inflammatory responses, but the impacts of such strategies on airway structure remain largely unknown.

Corticosteroids

Inhaled corticosteroids (ICSs) are a first-line asthma therapy recommended by the NHLBI and WHO [1]. Their potency to control inflammation is well-documented, but effects of CS on airway remodeling are as yet undefined. Several CSs have anti-proliferative effects in vitro on airway smooth muscle cells [123] and lung fibroblasts [124,125]. Treating cells isolated from sputum of asthmatic patients with flunisolide in culture reduced their secretion of TGF-β, MMP-9, and TIMP-1 [126]. These findings suggest CSs may effectively suppress subepithelial fibrosis. Clinical studies agree with these in vitro data: 1–2 years of ICS therapy at intermediate–high doses reduced the thickness of the subepithelial reticular layer, indicating ability of such treatment to regulate airway remodeling [94,127]. Ward et al. also attributed approximately 60% of the observed improvement in AHR in ICS-treated asthma patients to a reduction in reticular basement membrane thickness [127], pointing to a substantial contribution of airway remodeling to asthma. Another clinical study revealed reduced basement membrane thickness and vascularity after 6-week-treatment with daily fluticasone propionate at a dose of 1000 μg (but not 200 μg) [9]. In contrast, inhaled [128,129] or oral [130] CS treatment of shorter duration showed more modest or no effect on subepithelial collagen deposition or metalloproteolytic equilibrium in patients [128–130]. Two-week-treatment with oral CS failed to suppress TGF-β expression [130], perhaps accounting for the persistent subepithelial fibrosis observed.

CSs may also promote recovery of epithelial integrity in asthma. An in vitro study demonstrated dexamethasone’s ability to block cytokine-induced AEC apoptosis [131]. Following 3-month inhaled budesonide treatment, asthmatic individuals displayed increased proportions of ciliated epithelial cells in their airway tissues [132]. Inhaled budesonide was also associated with decreased numbers of goblet cells [133]. Likewise, allergen-stimulated goblet cell hyperplasia was prevented by intratracheally administered CSs (ciclesonide or fluticasone) in rats [134]. ICS treatments reduced vascularity in the airways of asthmatic patients [9,135–137]. In sum, available data on CS effects on airway remodeling are encouraging. Direct comparisons of drug concentrations and treatment duration in different combinations may further inform how CSs regulate airway structure.

β2-adrenergic receptor agonists

The roles of β2-adrenergic receptor agonists in airway remodeling are uncertain. Young et al. found anti-proliferative effects of salbutamol and salmeterol on cultured airway smooth muscle cells [123], whereas Burgess et al. found that long-acting β2-adrenergic receptor agonist monotherapy (formoterol or salmeterol) failed to block TGF-β-induced ECM, growth factor, or cytokine expression in airway smooth muscle cells from asthmatic or non-asthmatic individuals [138]. A combination of β2-adrenergic receptor agonists and ICSs was found more successful than either drug type alone in controlling fibroblast proliferation [124] and excessive matrix production by cultured human fibroblasts [139]. Asthmatic patients who received salmeterol as a supplement to ongoing ICS treatment also showed a decrease in subepithelial vascularity [140]. Reduced levels of MMP-9, TIMP-1, and TGF-β in sputum samples along with decreased airway wall thickness were seen after budesonide-formoterol treatment [141], highlighting the potential of combination therapy to correct asthma-associated abnormal tissue remodeling.

Phosphodiesterase inhibitors

Phosphodiesterase inhibitors block inactivation of intracellular cAMP and cGMP and display anti-inflammatory actions. Several of these drugs promote favorable effects on airway remodeling. For example, roflumilast reduced epithelial thickening and subepithelial collagen deposition in ovalbumin-sensitized and chronically antigen-challenged mice [142]. Theophylline decreased TGF-β-stimulated expression of collagen in normal human lung fibroblasts and also reduced fibroblast proliferation and differentiation into myofibroblasts as indicated by reduced α-SMA expression [143]. The type 3-selective phosphodiesterase inhibitor siguazodan suppressed proliferation of primary human airway smooth muscle cells in vitro [144], while LASSBio596, an agent designed to target two major types of lung phosphodiesterase, was found comparable with dexamethasone in ability to control many of structural and mechanical changes of airways in a murine model of chronic asthma [145]. These preclinical findings are promising, but clinical data are as yet lacking to establish any clinical improvements in airway structure resulting from treatment with phosphodiesterase inhibitors.

Anti-IgE therapy

IgE contributes to allergic asthma development by modulating release of mediators from inflammatory cells and thereby initiating the inflammatory cascade. The recombinant humanized anti-IgE antibody omalizumab sequesters and reduces free circulating IgE and alleviates airway inflammation [120,146,147], but data are scarce regarding its effect on airway remodeling. Morphometric analysis of bronchial biopsies from asthma patients treated with omalizumab for 3 years showed reduced reticular basement membrane thickness along with decreased eosinophilic infiltration [148]. In vitro, omalizumab reduced antigen-stimulated expression and secretion of TGF-β by human bronchial epithelial cells [149]. Furthermore, treatment for 1 year with omalizumab in patients with severe persistent allergic asthma reduced the levels of endothelin-1, which promotes smooth muscle cell proliferation, in exhaled breath condensates [150]. Omalizumab treatment also allowed reduction of ICS dosages in some individuals. Its potential as an airway remodeling-targeting drug is promising, but many of these studies only address omalizumab’s ability to regulate presumptive mediators of airway restructuring. Thus, more rigorous, direct assessment of its effects on tissue remodeling in allergic asthma is warranted.

Cytokine modulators

Eosinophils promote structural modifications in airways by secreting key mediators including TGF-β, VEGF, MMP-9, TIMP-1, and IL-13 [151]. IL-5 is a cytokine important for eosinophilopoiesis, and a humanized monoclonal antibody to IL-5 was found to reduce the numbers of eosinophils in blood and sputum of asthmatic individuals [152]. Similarly, asthma patients who received mepolizumab showed reduced eosinophils in airway tissue, procollagen III expression in the subepithelial reticular basement membrane, and TGF-β1 concentration in BAL fluids [151]. In a murine model of atopic asthma, the anti-IL-5 antibody TRFK5 not only suppressed eosinophil infiltration into the airways, but also prevented allergen-induced subepithelial fibrosis [153]. Importantly, in a randomized, placebo-controlled, parallel-group study of patients with recurrent, CS-refractory asthma, mepolizumab treatment yielded greater reduction in airway wall area and total airway area than placebo [154].

In addition to IL-5, IL-4, and IL-13 are critical regulators of allergic inflammation and possibly of airway remodeling, but studies assessing their effects on airway remodeling are currently lacking. Nevertheless, IL-4- and IL-13-deficiency prevented the expected increase in collagen deposition and goblet cell hyperplasia in allergen-exposed mice [155], supporting the potential promise of targeting these cytokines in asthma. Collectively, these data suggest that blocking or neutralizing pro-inflammatory Th2 cytokines may be valuable strategies not only to alleviate inflammation but also to prevent or reverse structural alterations in the airways, justifying further research.

Leukotriene receptor antagonists

Leukotriene receptor antagonists comprise another group of anti-inflammatory molecules that may regulate airway remodeling. Montelukast suppressed allergen-induced goblet cell hyperplasia, mucus hypersecretion, airway smooth muscle thickening, and subepithelial collagen deposition/fibrosis as well as epithelial cell desquamation in ovalbumin-sensitized/challenged mice [156,157]. Asthmatic patients treated with montelukast for 8 weeks also resisted an allergen-induced increase in myofibroblast counts [158]. It will be important to determine how other components of airway remodeling are affected by leukotriene receptor antagonism, and what long-term outcomes such treatments may evoke.

Tyrosine kinase inhibitor

Nintedanib is an inhibitor of multiple tyrosine kinases that has been approved for treatment of idiopathic pulmonary fibrosis (IPF). In a murine model of ovalbumin-induced chronic asthma, nintedanib treatment suppressed allergen-induced increase in vascularity, goblet cell hyperplasia, mucus hypersecretion, total collagen content, and airway smooth muscle area in lung tissues [159]. In mice with ovalbumin-induced acute asthma, nintedanib treatment blocked allergen-stimulated increases in TGF-β levels [160], with effectiveness comparable to that of dexamethasone. These findings indicate that nintedanib has potential to target airway remodeling in asthma, but the applicability of its therapeutic benefits in human asthma patients remains to be tested.

Peroxisome proliferator-activated receptor agonists

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear hormone receptor that regulates multiple cell types involved in asthma and other inflammatory diseases [161–164]. In addition to their anti-inflammatory effects, PPARγ agonists and activation have been shown to mitigate multiple features of airway remodeling. Pioglitazone reduced mucus hypersecretion in a murine model of allergic asthma [165]. Ciglitazone likewise decreased mucus overproduction and collagen accumulation in mice [166,167]. Human airway smooth muscle cell proliferation was inhibited, and apoptosis was induced by either 15d-PGJ2 or ciglitazone in vitro [168]. Agonists of PPARγ prevent differentiation of human lung fibroblasts into myofibroblasts and suppress their collagen secretion [169], suggesting ability to reduce subepithelial fibrosis. Also, rosiglitazone and pioglitazone reportedly reduced MMP-9 activity and expression in TNF-α- and phorbol 12-myristate 13-acetate-stimulated human bronchial epithelial cells [170]. These preclinical data are reinforced by those from a large retrospective cohort study that analyzed asthmatic individuals being treated for their diabetes with thiazolidinediones [171]. That study found thiazolidinedione treatment associated with reduced risks of asthma exacerbations and oral steroid prescriptions. Prospective studies of thiazolidinediones’ influence on airway structure in a broader population of asthma-affected individuals would inform about the potential promise of PPARγ agonists as asthma therapies. It will likewise be useful to assess the functions of other PPAR subtypes (PPARα and PPARβ/δ), and the effects of their activation/agonists on airway remodeling [161–164].

Bronchial thermoplasty

This treatment modality applies controlled radiofrequency energy to alleviate smooth muscle hypertrophy/hyperplasia in individuals with severe asthma. Despite short-term risk of adverse events, the procedure has yielded multiple clinical benefits and improved quality of life [172–174]. Besides reducing smooth muscle mass, bronchial thermoplasty was found to decrease subepithelial collagen deposition [175] and thickening of the basement membrane layer [176]. Therapeutic efficacy of this novel treatment is promising. Additional studies to assess its histopathological outcomes (e.g., airway epithelial integrity, goblet cell hyperplasia/metaplasia, mucus hypersecretion) will further inform the balance of its potential benefits vs. risks.

Conclusions

Airway remodeling leads to progressive loss of lung function. In addition, accumulating evidence supports the emerging concept that inflammation and remodeling occur in parallel and promote each other, thus perpetuating asthma-associated pathology (Figure 1). Accordingly, it is recommended that asthma therapies (Table 1) be directed at both inflammation and structural changes. Future research should be prioritized toward deciphering which structural modifications contribute to which pathophysiological features of asthma and elucidating the mediating mechanisms. Research to establish structure–function relationships in asthma would advance development of diagnostic tools and facilitate early recognition and intervention.

Table 1
Summary of therapeutic agents that target airway remodeling
TherapeuticsPrimary effects on airway remodelingReferences
Corticosteroids Cortisol or
Beclomethasone dipropionate 
Inhibited proliferation of bovine tracheal smooth muscle cells [123
 Beclomethasone dipropionate • Inhibited proliferation of primary human lung fibroblasts
• Reduced vascularity in airways of asthma patients 
[124]
[135,136
 Mometasone furoate or Dexamethasone Inhibited proliferation of human fetal lung fibroblast cell line [125
 Flunisolide Reduced secretion of TGF-β, MMP-9, and TIMP-1 from cells in sputum of asthma patients [126
 Fluticasone propionate • Reduced subepithelial reticular basement membrane thickness in the airways of asthma patients
• Reduced vascularity in the airways of asthma patients 
[9,127]
[9,137
 Dexamethasone Inhibited cytokine-induced apoptosis of pulmonary epithelial cell line [131
 Budesonide • Increased the proportion of ciliated epithelial cells in airways of asthma patients
• Decreased goblet cell numbers 
[132]
[133
 Ciclesonide or
Fluticasone propionate 
Reduced goblet cell hyperplasia in rat airways [134
β2-Adrenergic receptor agonists Salbutamol or Salmeterol Inhibited proliferation of bovine tracheal smooth muscle cells [123
 Salbutamol or Formoterol (combined with Beclomethasone dipropionate) Inhibited proliferation of primary human lung fibroblasts [124
 Formoterol (combined with Budesonide) • Inhibited TGF-β-stimulated production of extracellular proteoglycans in human lung fibroblast cell line
• Reduced secretion of TGF-β, MMP-9, and TIMP-1 from cells in sputum and decreased airway wall thickness in asthma patients 
[139]
[141
 Salmeterol (combined with ICS) Decreased subepithelial vascularity in the airways of asthma patients [140
Phosphodiesterase inhibitors Roflumilast Reduced epithelial thickening and subepithelial collagen deposition in ovalbumin-sensitized and chronically antigen-challenged mice [142
 Theophylline Decreased TGF-β-stimulated expression of collagen in normal human lung fibroblasts and reduced their proliferation and differentiation into myofibroblasts [143
 Siguazodan Inhibited proliferation of primary human airway smooth muscle cells [144
 LASSBio596 • Blocked airway remodeling in a murine model of chronic asthma (details not provided)
• Inhibited mechanical changes in lung parenchyma and airways in a murine model of chronic asthma 
[145
Anti-IgE therapy Omalizumab Reduced reticular basement membrane thickness and decreased eosinophil infiltration in bronchial tissues from asthma patients [148
  Reduced antigen-stimulated expression and secretion of TGF-β by human bronchial epithelial cells [149
  Reduced endothelin-1 levels in exhaled breath condensates from patients with severe persistent allergic asthma [150
Anti-IL-5 antibody SB-240563 (mepolizumab) Reduced the numbers of eosinophils in blood and sputum of asthma patients [152
 Mepolizumab • Reduced the numbers of eosinophils in airway tissues, procollagen III expression in the subepithelial reticular basement membrane, and TGF-β1 concentration in BAL fluid of asthma patients
• Reduced airway wall area and total airway area in patients with refractory asthma 
[151]
[154
 TRFK5 Suppressed eosinophil infiltration into airways and blocked allergen-induced subepithelial fibrosis in a murine model of atopic asthma [153
Leukotriene receptor antagonists Montelukast • Suppressed allergen-induced goblet cell hyperplasia, mucus hypersecretion, airway smooth muscle thickening, subepithelial collagen deposition/fibrosis, and epithelial cell desquamation in ovalbumin-sensitized/challenged mice
• Blocked allergen-induced elevations of myofibroblast counts in asthma patients 
[156,157]
[158
Tyrosine kinase inhibitor Nintedanib • Suppressed allergen-induced increases in vascularity, goblet cell hyperplasia, mucus hypersecretion, total collagen content, and airway smooth muscle area in lungs in a mouse model of ovalbumin-induced chronic asthma
• Blocked allergen-stimulated increase in TGF-β levels in BAL fluid in a murine model of ovalbumin-induced acute asthma 
[159]

[160
PPAR agonists Pioglitazone Reduced mucus hypersecretion in lungs in a murine model of allergic asthma [165
 Ciglitazone Reduced airway mucus overproduction and collagen accumulation in lungs in a murine model of allergic asthma [166,167
 15d-PGJ2 or Ciglitazone Inhibited proliferation and induced apoptosis of human airway smooth muscle cells [168
 15d-PGJ2, Rosiglitazone, or Ciglitazone Blocked differentiation of human lung fibroblasts into myofibroblasts and their secretion of collagen [169
 Pioglitazone or Rosiglitazone Reduced MMP-9 expression and activity in TNF-α- and phorbol 12-myristate 13-acetate-stimulated human bronchial epithelial cells [170
Bronchial thermoplasty  • Reduced airway smooth muscle mass in asthma patients and decreased subepithelial collagen deposition in bronchial tissues
• Reduced the thickening of subepithelial basement membrane in bronchial tissues of asthma patients 
[175]
[176
TherapeuticsPrimary effects on airway remodelingReferences
Corticosteroids Cortisol or
Beclomethasone dipropionate 
Inhibited proliferation of bovine tracheal smooth muscle cells [123
 Beclomethasone dipropionate • Inhibited proliferation of primary human lung fibroblasts
• Reduced vascularity in airways of asthma patients 
[124]
[135,136
 Mometasone furoate or Dexamethasone Inhibited proliferation of human fetal lung fibroblast cell line [125
 Flunisolide Reduced secretion of TGF-β, MMP-9, and TIMP-1 from cells in sputum of asthma patients [126
 Fluticasone propionate • Reduced subepithelial reticular basement membrane thickness in the airways of asthma patients
• Reduced vascularity in the airways of asthma patients 
[9,127]
[9,137
 Dexamethasone Inhibited cytokine-induced apoptosis of pulmonary epithelial cell line [131
 Budesonide • Increased the proportion of ciliated epithelial cells in airways of asthma patients
• Decreased goblet cell numbers 
[132]
[133
 Ciclesonide or
Fluticasone propionate 
Reduced goblet cell hyperplasia in rat airways [134
β2-Adrenergic receptor agonists Salbutamol or Salmeterol Inhibited proliferation of bovine tracheal smooth muscle cells [123
 Salbutamol or Formoterol (combined with Beclomethasone dipropionate) Inhibited proliferation of primary human lung fibroblasts [124
 Formoterol (combined with Budesonide) • Inhibited TGF-β-stimulated production of extracellular proteoglycans in human lung fibroblast cell line
• Reduced secretion of TGF-β, MMP-9, and TIMP-1 from cells in sputum and decreased airway wall thickness in asthma patients 
[139]
[141
 Salmeterol (combined with ICS) Decreased subepithelial vascularity in the airways of asthma patients [140
Phosphodiesterase inhibitors Roflumilast Reduced epithelial thickening and subepithelial collagen deposition in ovalbumin-sensitized and chronically antigen-challenged mice [142
 Theophylline Decreased TGF-β-stimulated expression of collagen in normal human lung fibroblasts and reduced their proliferation and differentiation into myofibroblasts [143
 Siguazodan Inhibited proliferation of primary human airway smooth muscle cells [144
 LASSBio596 • Blocked airway remodeling in a murine model of chronic asthma (details not provided)
• Inhibited mechanical changes in lung parenchyma and airways in a murine model of chronic asthma 
[145
Anti-IgE therapy Omalizumab Reduced reticular basement membrane thickness and decreased eosinophil infiltration in bronchial tissues from asthma patients [148
  Reduced antigen-stimulated expression and secretion of TGF-β by human bronchial epithelial cells [149
  Reduced endothelin-1 levels in exhaled breath condensates from patients with severe persistent allergic asthma [150
Anti-IL-5 antibody SB-240563 (mepolizumab) Reduced the numbers of eosinophils in blood and sputum of asthma patients [152
 Mepolizumab • Reduced the numbers of eosinophils in airway tissues, procollagen III expression in the subepithelial reticular basement membrane, and TGF-β1 concentration in BAL fluid of asthma patients
• Reduced airway wall area and total airway area in patients with refractory asthma 
[151]
[154
 TRFK5 Suppressed eosinophil infiltration into airways and blocked allergen-induced subepithelial fibrosis in a murine model of atopic asthma [153
Leukotriene receptor antagonists Montelukast • Suppressed allergen-induced goblet cell hyperplasia, mucus hypersecretion, airway smooth muscle thickening, subepithelial collagen deposition/fibrosis, and epithelial cell desquamation in ovalbumin-sensitized/challenged mice
• Blocked allergen-induced elevations of myofibroblast counts in asthma patients 
[156,157]
[158
Tyrosine kinase inhibitor Nintedanib • Suppressed allergen-induced increases in vascularity, goblet cell hyperplasia, mucus hypersecretion, total collagen content, and airway smooth muscle area in lungs in a mouse model of ovalbumin-induced chronic asthma
• Blocked allergen-stimulated increase in TGF-β levels in BAL fluid in a murine model of ovalbumin-induced acute asthma 
[159]

[160
PPAR agonists Pioglitazone Reduced mucus hypersecretion in lungs in a murine model of allergic asthma [165
 Ciglitazone Reduced airway mucus overproduction and collagen accumulation in lungs in a murine model of allergic asthma [166,167
 15d-PGJ2 or Ciglitazone Inhibited proliferation and induced apoptosis of human airway smooth muscle cells [168
 15d-PGJ2, Rosiglitazone, or Ciglitazone Blocked differentiation of human lung fibroblasts into myofibroblasts and their secretion of collagen [169
 Pioglitazone or Rosiglitazone Reduced MMP-9 expression and activity in TNF-α- and phorbol 12-myristate 13-acetate-stimulated human bronchial epithelial cells [170
Bronchial thermoplasty  • Reduced airway smooth muscle mass in asthma patients and decreased subepithelial collagen deposition in bronchial tissues
• Reduced the thickening of subepithelial basement membrane in bronchial tissues of asthma patients 
[175]
[176

Critically, reliable/established biomarkers to enable monitoring airway remodeling are scarce [29]. Periostin, a secreted protein expressed in bronchial epithelial cells and fibroblasts, has been suggested as a serum biomarker for airway wall thickness and as sputum eosinophilia [177]. Similarly, galectin-3 has been proposed as a biomarker of reticular basement membrane thickness, eosinophilia, and smooth muscle protein levels in the omalizumab-responding galectin-3-positive subset of asthma patients [148]. Vigorous efforts to develop or identify new biomarkers of airway remodeling induction, progression, and therapy responsiveness are urgently needed, to enhance success in improving therapies to reverse or prevent airway structural pathology and asthma outcomes.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by a merit review award from the U.S. Department of Veterans Affairs and a National Institutes of Health Grant [grant number AI125338 (to R.C.R.)].

Author Contribution

A.B. conducted the literature review and drafted the manuscript. A.T.R. and S.P.L. provided important insights and contributions to the manuscript’s content. R.C.R. provided critiques on the manuscript, contributed expert advice on the topic, and played a role in editing. All authors read and approved the final manuscript.

Abbreviations

     
  • AEC

    airway epithelial cell

  •  
  • AHR

    airway hyperresponsiveness

  •  
  • BAL

    bronchoalveolar lavage

  •  
  • CS

    corticosteroid

  •  
  • CT

    computed tomography

  •  
  • ECM

    extracellular matrix

  •  
  • EMT

    epithelial–mesenchymal transition

  •  
  • EMTU

    epithelial–mesenchymal trophic unit

  •  
  • ICS

    inhaled corticosteroid

  •  
  • IL

    interleukin

  •  
  • MMP

    matrix metalloproteinase

  •  
  • PAS

    periodic acid-Schiff

  •  
  • PPAR

    peroxisome proliferator-activated receptor

  •  
  • SMA

    smooth muscle actin

  •  
  • TGF-β

    transforming growth factor-β

  •  
  • Th2

    T helper 2

  •  
  • TIMP

    tissue inhibitor of metalloproteinase

  •  
  • TLR

    Toll-like receptor

  •  
  • VEGF

    vascular endothelial growth factor

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