The pathogenesis of asthma is complex and multi-faceted. Asthma patients have a diverse range of underlying dominant disease processes and pathways despite apparent similarities in clinical expression. Here, we present the current understanding of asthma pathogenesis. We discuss airway inflammation (both T2HIGH and T2LOW), airway hyperresponsiveness (AHR) and airways remodelling as four key factors in asthma pathogenesis, and also outline other contributory factors such as genetics and co-morbidities. Response to current asthma therapies also varies greatly, which is probably related to the inter-patient differences in pathogenesis. Here, we also summarize how our developing understanding of detailed pathological processes potentially translates into the targeted treatment options we require for optimal asthma management in the future.

Introduction

Asthma is a common respiratory condition, affecting an estimated 300 million people worldwide [1]. Clinically, it is characterized by a typical constellation of symptoms (cough, wheeze, shortness of breath and chest tightness) in combination with evidence of expiratory airflow limitation [2]. Symptoms and airflow limitation can be extremely variable, both between patients and within an individual patient at different points in time [2].

The pharmacological treatment of asthma involves adding new therapies or increasing the dose of existing medications in a stepwise approach, such that more severe asthma is often treated with several medications targeting different mechanistic pathways [24]. Yet despite this approach, some patients continue to suffer persistent symptoms and frequent exacerbations, and are therefore termed ‘difficult-to-treat’ or ‘refractory’ asthma [2,5]. These patients require a holistic multi-disciplinary approach to their management [3], but it is becoming increasingly clear that a detailed understanding of the underlying pathogenesis of the individual patients’ disease is vital in directing their care. As additional new and expensive treatments become more widely available, this tailored approach to treatment becomes ever more critical.

There is significant heterogeneity between patients with asthma, not only in clinical characteristics and disease severity, but also in relation to the degree and pattern of underlying airway inflammation, airway hyperresponsiveness (AHR) and airway remodelling [5,6]. Various ‘phenotype’ models have been developed, based on clinical characteristics [6,7], but underlying disease mechanisms are not necessarily reflected in these outwardly observable features. Two patients with very different asthma phenotypes and severities may have the same underlying pathogenesis; while conversely, two patients with a similar clinical picture may have greatly contrasting disease mechanisms. Differentiating patients according to the underlying functional and pathological disease process, or ‘endotype’, may hold much greater utility in choosing the most effective treatment strategy [8,9].

Pathogenesis of asthma

The pathogenesis of asthma involves a complex web of interacting factors at all levels and scales of the disease, from genetic to cellular, to tissue, to organ. It is complicated further by the effects of environmental influences, pharmacotherapy and non-asthma related patient factors such as co-morbidity and lifestyle(Figure 1). Here, we will consider the pathogenesis of asthma using four chief disease domains: airway inflammation (both T2HIGH and T2LOW), AHR and airway remodelling. Each of these elements spans the scales of disease described above, whilst also overlapping and impacting on one another. To further complicate the picture, these disease elements not only co-exist within an individual asthmatic, but their interactions over time, or in response to an exposure or intervention, are often variable (Figure,2).

Scales of disease of asthma with examples of disease heterogeneity at all levels from gene through to patient.

Figure 1
Scales of disease of asthma with examples of disease heterogeneity at all levels from gene through to patient.

Scales of disease of asthma with examples of disease heterogeneity at all levels from gene through to patient.

Figure 1
Scales of disease of asthma with examples of disease heterogeneity at all levels from gene through to patient.

Scales of disease of asthma with examples of disease heterogeneity at all levels from gene through to patient.

The heterogeneity of asthma immunopathology segmented into eosinophilic (allergic and non-allergic) versus non-eosinophilic (neutrophilic T1/17 and pauci-granulocytic) and mixed granulocytic inflammation illustrating the mechanisms and characteristic pathological features.

Figure 2
The heterogeneity of asthma immunopathology segmented into eosinophilic (allergic and non-allergic) versus non-eosinophilic (neutrophilic T1/17 and pauci-granulocytic) and mixed granulocytic inflammation illustrating the mechanisms and characteristic pathological features.

The heterogeneity of asthma immunopathology segmented into eosinophilic (allergic and non-allergic) versus non-eosinophilic (neutrophilic T1/17 and pauci-granulocytic) and mixed granulocytic inflammation illustrating the mechanisms and characteristic pathological features.

Figure 2
The heterogeneity of asthma immunopathology segmented into eosinophilic (allergic and non-allergic) versus non-eosinophilic (neutrophilic T1/17 and pauci-granulocytic) and mixed granulocytic inflammation illustrating the mechanisms and characteristic pathological features.

The heterogeneity of asthma immunopathology segmented into eosinophilic (allergic and non-allergic) versus non-eosinophilic (neutrophilic T1/17 and pauci-granulocytic) and mixed granulocytic inflammation illustrating the mechanisms and characteristic pathological features.

The onset of asthma symptoms can occur at any age. Children who develop asthma during their early years may continue to suffer asthma as an adult, but a proportion of them will have a full resolution of their symptoms during childhood. Contrastingly, some asthmatic adults have no symptoms in childhood and only develop the disease later in life. Risk factors in early life that increase an individual’s risk of developing asthma, and influence whether asthma persists into adulthood, include female gender, smoke exposure, atopy and severity of childhood symptoms [10]. Regardless of the pattern of onset, both adults and children with asthma can have a relapsing and remitting nature to their disease at different times of their life, sometimes with very prolonged periods of time between episodes of illness. Even during periods of symptom remission, a significant proportion of patients still show evidence of airways hyperresponsiveness or airway remodelling [10]. This highlights the discord often present between symptoms and disease activity, and emphasizes the importance of ongoing treatment and monitoring, even in periods of relative disease stability, in order to minimize a patient’s future risk from undertreated asthma. Importantly, at the point of disease onset asthma can be mild, moderate or severe [10], and severe asthma is not necessarily a gradual progression from mild to moderate, to severe. This vast variability in disease onset and clinical course is evidence that asthma is not simply an outward manifestation of an entirely intrinsic process, but that a range of interacting intrinsic and extrinsic factors are responsible for disease development and progress. Here, we aim to summarize these complex processes and discuss the implications they have for delivering tailored precision medicine.

Genetics

A genetic susceptibility to asthma has been known for many years, with strong family trends towards asthma and other atopic diseases. A number of large genome-wide association studies (GWAS) have been undertaken to identify specific sets of asthma-related genes, and to characterize links between the genetic and clinical characteristics of the disease.

Numerous gene associations for asthma have been identified, including single-nucleotide polymorphisms (SNPs) found on chromosome 2 (IL18R1 and IL1RL1), chromosome 6 (HLA-DQ region of the major histocompatibility complex gene), chromosome 9 (flanking the IL33 gene), chromosome 15 (SMAD3) and chromosome 22 (IL2RB) [11,12]. The IL33 gene encodes for the production of the cytokine interleukin (IL)-33, which is present in airway epithelial cells, and particularly in damaged tissues [11]. IL-33 stimulates production of Th2-associated inflammatory cytokines IL-4, IL-5 and IL-13, which play numerous important roles in asthma pathogenesis (discussed in detail below). The IL18R1 and IL1RL1 locus on chromosome 2 also appears to be functionally related to IL-33 activity, as IL1RL1 encodes for the ST2 receptor, to which IL-33 binds to exert its various pro-inflammatory effects [11]. SMAD3 and IL2RB may have regulatory roles in healing and repair [11], and are therefore potentially important in airway remodelling.

Several SNPs on chromosome 17q21 show different associations between childhood onset asthma and adult onset asthma [11,13]. One such gene, which shows strong correlations with the development of childhood asthma, is ORMDL3 [13], and ORM genes may have a role in airway inflammation, although this has not yet been shown in human subjects. The CDHR3 gene is also associated with the presence of asthma in children aged between 2 and 6 years old [14]. CDHR3 may be implicated in airway remodelling, and in particular with the regulation of epithelial integrity, and could therefore be important in airway responses to inhaled insults such as pathogens and pollutants [14]. Differential expression of the CDHR3 gene in this group of young children also highlights the early age at which remodelling changes in the airway can occur.

ORMDL3 and IL1RL1/IL18R1 have been validated as significant gene associations in a cohort of severe asthmatics, although no genes specific to severe asthma have so far been identified [15]. However, some of the gene SNPs described here correlate with the risk of hospitalization due to severe asthma exacerbation [14], thereby potentially implicating genetic factors in the development of specific phenotype traits such as exacerbation susceptibility and resistance to therapy. Correlations have also been identified between specific gene expression and patterns of lung function decline [16], although further work is needed in this area.

The possibility of targeted gene therapies for asthma in the future carries significant appeal, with the theoretical potential to treat, cure or even prevent asthma in genetically susceptible individuals. However, despite the identification of genes associated with asthma, the presence of these genes has not proven particularly sensitive or specific as a predictor of asthma diagnosis in an individual patient, even when multiple genes are used in combination [11]. Genetic differences have also not been shown to be directly related to other important clinical markers such as serum Immunoglobulin (Ig) E levels [11]. This illustrates how genetics cannot be considered in isolation, are only one of many important host and environmental factors, and may not be clinically relevant to a significant proportion of asthmatic patients. Even if gene therapies become a reality for asthma, these other disease factors may limit their application and success.

T2HIGH inflammation

T2HIGH-mediated eosinophilic disease, heavily consequent on T-cell polarization by the transcription factor GATA3, is the dominant inflammatory profile across the asthma spectrum [5,17,18]. Sputum eosinophilia is a feature in up to 80% of corticosteroid naïve, and 50% of corticosteroid treated asthmatics [19,20]. In addition to blood and/or tissue eosinophilia, these patients also exhibit high levels of T2 cytokines such as interleukins IL-4, IL-5 and IL-13 [5,17,18], which are critical to the regulation of eosinophilic inflammation.

T2HIGH eosinophilic inflammation is most commonly associated with atopy, and allergic asthma accounts for most cases in children and approximately half of cases in adults. The hallmark of atopic and allergic disease is a raised level of serum IgE, although the presence of high levels of IgE in isolation is neither a good predictive marker for the development of asthma nor whether T2-mediated inflammation is the dominant disease profile in those who do have asthma [21]. Sputum eosinophilia has been shown to be a more robust marker of T2-mediated disease, and can be reliably reproduced in the short term [22,23]. However, the inflammatory profile of some asthmatics can vary greatly over time. For example, in a study of 995 asthma patients, 31% of subjects were found to have an intermittent eosinophilia compared with 22% with a persistent eosinophilia [18].

There is some evidence to suggest that almost all asthmatics have an element of T2HIGH disease, even in the absence of an obviously demonstrable eosinophilia. Firstly, reduction of T2-inflammation suppressing corticosteroids in apparently non-eosinophilic asthmatics leads to the emergence of detectable eosinophil levels in most cases [24]. Secondly, eosinophils are cleared from the lung by macrophages, and the rate of clearance can be determined by measurement of the amount of eosinophil proteins in airway macrophages. In apparently non-eosinophilic patients, examination of eosinophil proteins in airway macrophages confirms the presence of eosinophil clearance processes, suggesting some eosinophilic inflammation that is being controlled by therapy [24].

Conversely, some patients have high sputum eosinophil counts but low levels of airway macrophage eosinophil clearance, suggesting treatment resistance due to either macrophage dysfunction or inadequate quantities of steroid reaching the airways [24]. Those severe asthmatics with persistent T2HIGH inflammation and a significant sputum eosinophilia are more likely to suffer from uncontrolled asthma, and have a high risk of asthma exacerbation [25]. Similarly, serum periostin is another marker of T2 activity, and higher periostin levels are associated with a greater exacerbation frequency [26]. The use of a composite biomarker score derived from blood eosinophil, serum periostin and exhaled nitric oxide values to wean corticosteroid therapy is currently being evaluated as part of the RASP-UK clinical trial [27].

As highlighted above, the eosinophil is central to T2HIGH inflammation. Eosinophil function is largely regulated by a complex immune response involving numerous stimulatory and inhibitory inflammatory cytokines and effector cells; some of which are potential targets for novel therapies.

OX40 and its ligand OX40L, and epithelial-derived thymic stromal lymphopoietin (TSLP), are early stimulators of T2-mediated inflammatory processes. They promote both the innate and adaptive immune responses, and the activity of both TSLP and OX40L is elevated in response to inhaled allergens [28]. Following allergen exposure, TSLP originating from the epithelium directly stimulates mast cell activity and triggers maturation of immature dendritic cells. Mature dendritic cells produce OX40L and migrate into lymph nodes. Here, they cause differentiation of naïve CD4+ T cells into inflammatory Th2 cells (with subsequent promotion of T2 inflammatory cytokines such as ILs as described below), and blockade of the TSLP/OX40 axis has been shown to reduce Th2-related inflammation [28].

OX40L inhibition may potentially be disease modifying and prevent the development of allergic asthma in early life, as it could interrupt the allergic sensitization process. However, this is difficult to test as it would require identifying and treating susceptible children (such as those with childhood wheeze), and as such has not been investigated. When used in adults with established asthma anti-OX40L therapy does reduce serum IgE and sputum eosinophils but has no effect on allergen-induced airway responses [29], presumably because the sensitization process has already occurred. TSLP has a role in both allergic sensitization and also ongoing T2 inflammation, and so anti-TSLP treatment appears more promising. Treatment with a human anti-TSLP monoclonal antibody reduces blood and sputum eosinophil levels and lowers exhaled nitric oxide, as well as improving lung function measures after allergen challenge [30]. Thus, anti-TSLP treatment holds the potential to be both disease modifying and disease controlling, and further clinical trials are eagerly awaited.

Th2 cells release inflammatory cytokines and activate a series of downstream processes that play key roles in eosinophilic inflammation [21]. Eosinophils develop in the bone marrow from pluripotent CD34+ progenitor stem cells, which differentiate into eosinophils under the influence of granulocyte monocyte colony-stimulating factor (GM-CSF) and IL-3 in the early stages, and IL-5 in the later stages [31]. CD34+ cells bearing receptors for IL-3 and IL-5 have been shown to be present in higher numbers in the bone marrow of subjects with asthma in response to an allergen challenge [32,33], suggesting an acute phase response in the bone marrow to produce and develop additional eosinophils following allergic stimulus. The continued influence of IL-5 stimulates release of mature eosinophils from the bone marrow into circulating blood.

Once in the circulation eosinophils remain relatively inactive until they are primed. Priming increases their responsiveness to chemotaxis, degranulation and cytokine production and is also mediated by cytokines IL-3, IL-5 and GM-CSF [34,35]. Once primed, eosinophils move into the tissues under the influence of cytokines including IL-4 and IL-5 [36]. This process first requires the eosinophil to adhere to the vascular endothelium, from where they can migrate into the surrounding tissues. Interactions between integrins on the surface of eosinophils and adhesion receptors on the surface of vascular endothelium (such as P-selectin/P-selectin glycoprotein ligand-1 and VCAM-1 ligand) are critical to this process [37,38]. P-selectin and VCAM-1 are up-regulated by IL-4 and IL-13, again highlighting the critical role that cytokines IL-4, IL-5 and IL-13 play at several stages of eosinophil development and function [34,39,40].

Once adherence to the vascular endothelium has occurred, eosinophils are recruited into the lung mucosa under influence from the Eotaxin family of chemokines (CCL11, CCL24 and CCL26) [41]. These chemokines are up-regulated following allergen exposure, and act on the CCR3 chemokine receptor expressed on the eosinophil cell surface [41]. In the lung tissue, eosinophil survival is prolonged by IL-5 and GM-CSF produced locally [42].

The eosinophil itself regulates several aspects of the asthma response. Specific basic proteins released by eosinophils located in the lung tissue cause damage to the bronchial epithelium (eosinophil cationic protein – ECP, eosinophil-derived neurotoxin – EDN, eosinophil peroxidase – EPO, major basic protein – MBP), and MBP can also induce AHR (see below) [42]. Eosinophils are also a source of cysteinyl leukotrienes (along with basophils, mast cells, macrophages and myeloid dendritic cells) [42,43], which act primarily to cause bronchoconstriction, especially in asthmatics who are sensitive to aspirin [43].

D prostanoid receptor 2 (DP2), also called chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptor, has been implicated in allergic disease [44], and there is an increased level of DP2 positive inflammatory cells in patients with allergy and asthma [44]. Activated mast cells produce prostaglandin D2 (PGD2), which acts as a DP2 agonist [45], and elevated levels of PGD2 have been found in bronchoalveolar lavage samples from patients with asthma [44]. Furthermore, bronchial biopsy samples from patients with severe asthma have shown that DP2 positive cells are more frequent in the airway submucosa (particularly DP2 positive T cells), although less frequent in the bronchial epithelium, compared with healthy controls [44]. Activation of the DP2 receptor on Th2 cells has been shown to increase production of IL-2, IL-4, IL-5 and IL-13 [44], and promote eosinophil production, migration, recruitment into the lung tissue and survival. For this reason, the DP2 receptor is of interest as a therapeutic target, and a phase 2 study of a DP2 receptor antagonist showed a significant reduction in sputum eosinophil count in asthmatics with a baseline sputum eosinophilia compared with placebo [46]. Phase 3 trials are underway [47].

In the absence of allergy, eosinophilic inflammation can still arise in response to epithelial damage from inhaled pollutants and microbes. The epithelial ‘alarmins’ IL-25, IL-33 and TSLP are cytokines involved in the early stages of the inflammatory process. They are typically released in response to airway epithelial damage, and promote a T2 immune response even when allergy/atopy is not present.

Expression of IL-25 is greater in the tissues of patients with asthma, and IL-25 appears to be implicated in viral exacerbations of asthma. Asthmatic bronchial epithelial cells show a significantly heightened response in IL-25 production following infection with rhinovirus, and the magnitude of this response is also related to the degree of allergy within the patient [48]. Increased levels of IL-25 in response to rhinovirus infection are also associated with increases in IL-4, IL-5 and IL-13, suggesting that IL-25 mediated responses in bronchial epithelial cells result in release of T2 inflammatory cytokines and up-regulation of the T2 response [48]. In support of this, blocking IL-25 has been shown to reduce inflammation, AHR and T2 cytokine (IL-5 and IL-13) production [48].

IL-33 is released from necrotic epithelial cells, probably in response to injury from allergens, but also from microbes and airborne pollutants. It binds to the ST2 receptor present on wide range of effector cells, and exhibits a number of functions, including stimulating innate lymphoid type 2 cells (ILC2s) and Th2 cells to up-regulate secretion of IL-4, IL-5 and IL-13, thereby promoting eosinophil adhesion and survival [49]. IL-33/ST2 binding on mast cells, macrophages and basophils also up-regulates secretion of inflammatory cytokines [49]. In addition, IL-33 promotes the maturation of CD34+ cells into mast cells, and stimulates CD34+ progenitor cells to secrete IL-5, IL-6, IL-13, CXCL8, CCL1 and CCL17, resulting in a heightened allergic response [49]. Anti-IL-33 therapy is in phase 2 development [47].

In addition to allergen stimulation of the epithelium, TSLP is also up-regulated in response to mechanical epithelial injury, viruses and pro-inflammatory cytokines [50]. As described above, TSLP promotes T2 pathways through interactions with epithelial dendritic cells, but it also appears to exert a number of other direct functions including promotion of eosinophil survival and adhesion [50].

ILC2s have been implicated in non-atopic eosinophilic asthma. These recently identified cells are thought to be key mediators in the production of T2 cytokines and other mediators of tissue growth, inflammation and repair [51]. For example, mast cell-derived PGD2 interacts with ILC2s at the CRTH2 receptor to promote cytokine production [51]. Significantly higher amounts of ILC2s are present in the peripheral blood of asthmatics, suggesting that they play an important role in the pathogenesis of the disease [51], although evidence for their specific function in this role is relatively limited at present, partly due to practical difficulties in isolating specific ILC populations for study.

Advances in the understanding of T2HIGH inflammation have led to the development of several new treatments in asthma. Monoclonal antibodies against IL-4α subunit receptor, IL-5, IL-5α receptor and IL-13 have all shown clinical effectiveness in reducing eosinophilic inflammation. Blocking the α-subunit of the IL-4 receptor effectively inhibits both IL-4 and IL-13 activity, and studies using an anti-IL-4α monoclonal antibody (dupilumab) have shown an improvement in lung function and reduction in asthma exacerbation frequency, when used to treat moderate-to-severe asthmatics with a peripheral blood eosinophilia [52]. Similarly, binding IL-13 cytokines with the monoclonal antibodies lebrikizumab or tralokinumab has led to improvements in lung function [53,54]. Anti-IL-5 therapy (such as mepolizumab) is now licenced for use in severe eosinophilic asthma following trial evidence confirming reductions in both exacerbation rate and eosinophil levels when given to selected eosinophilic asthmatics with frequent exacerbations [5557]. Mepolizumab has also been shown to allow reduction of maintenance oral corticosteroid dose without loss of asthma control for patients taking oral corticosteroids [58]. Reslizumab (anti-IL-5) and benralizumab (anti-IL-5R) have shown similarly positive results in late stage clinical trials [5961]. Inhibition of the upstream ‘alarmins’ IL-25, IL-33 and TSLP may potentially be an even more effective therapeutic approach, by simultaneously reducing multiple downstream cytokines such as IL-4, IL-5, and IL-13, although trial evidence is not yet available to support this.

T2LOW inflammation

T2LOW inflammation is mediated predominantly by non-eosinophilic T1 and T17 pathways, with or without neutrophilic inflammation and oxidative stress [5,17,18]. Some asthmatics can switch between T2 and T17 inflammatory profiles, although T2 and T17 inflammation rarely occurs simultaneously [62]. Patients with isolated T2LOW neutrophilic airway inflammation (and absence of T2 cytokines) are more likely to have non-atopic late-onset asthma and an impaired response to inhaled corticosteroid treatment [17], although significant variation in clinical presentation can exist. Suppression of T2 inflammation up-regulates T17 immunity and increases T1/T17 cytokines [62], therefore some neutrophilic asthma may be iatrogenic, occurring as a consequence of T2-suppressing asthma therapies such as corticosteroids. This persistent neutrophilic inflammation, with or without co-existent T2 inflammation, may be an important contributor in asthma that is unresponsive or poorly responsive to steroids.

In addition to the ILC2 cells implicated in T2HIGH inflammation, ILC precursor cells can alternatively differentiate into ILC3 cells under the influence of transcription factors such as RORγT [51]. ILC3 cells are important regulators of T17 inflammation, producing IL-17A, IL-17F, IL-22, GM-CSF and tissue necrosis factor (TNF) [51].

One suggested mechanism for neutrophilic airway inflammation is bacterial colonization and the presence of bronchiectasis. However, a study of patients with severe asthma undergoing CT scans (most often for suspected concurrent bronchiectasis) found similar levels of sputum neutrophils in patients with and without CT-defined bronchiectasis [63], suggesting a neutrophilic sputum profile is not necessarily linked to the development of bronchiectasis, and that other factors are contributory.

The concept of bacterial colonization and secondary inflammation (independent of the presence of bronchiectasis) could explain the lack of efficacy of anti-neutrophil treatments (summarized in [64]) and suggestion of some efficacy from antibiotic therapy for T2LOW inflammation. Neutrophil function in asthmatics is impaired compared with health, which could lead to increased susceptibility to infection and asthma exacerbation [65]. Allergic inflammation has been shown to increase susceptibility for acute infection with the common respiratory pathogen Haemophilus influenzae to develop into chronic infection/colonization [66]. H. influenzae colonized asthmatics have increased levels of IL-17 with subsequent recruitment of additional neutrophils to the airway [66]. Despite increased neutrophil numbers in the airway of these patients, treatment with steroids appeared to further increase the bacterial load, suggesting traditional asthma therapy may actually worsen this situation where neutrophils are abundant in the airway but seemingly dysfunctional [66].

Treatment with the macrolide antibiotic azithromycin at low dose for 6 months reduces exacerbation frequency only in non-eosinophilic asthmatics; possibly suggesting that bacterial colonization in T2LOW patients is a significant contributing factor to their disease behaviour and exacerbation risk [67]. However, it is not clear whether this clinical benefit is related to the anti-bacterial or anti-inflammatory properties of macrolide antibiotics. In contrast, treatment with a 3-day course of azithromycin in response to an asthma exacerbation does not achieve any significant benefit in symptoms, quality of life or lung function during recovery from the exacerbation [68], although this was not a selected T2LOW population.

T17 cells produce the cytokines IL-17A, IL-17F and IL-22, which in turn promote the release of a range of other pro-inflammatory cytokines and chemokines, predominantly from neutrophils, but also from epithelial and vascular endothelial cells, fibroblasts and eosinophils [69]. These include IL-6, GM-CSF, CXCL10 and CXCL8. CXCL8 is a potent neutrophil chemokine, suggesting a role for T17 cytokines in neutrophilic airway inflammation, although this has not been conclusively proven [69]. IL-17A expression in the bronchial submucosa is elevated in mild-moderate asthma compared with healthy non-asthmatics, although this is not the case in severe asthma [69]. IL-17F expression in the bronchial submucosa is increased in all severities of asthma when compared with healthy controls [69]. It is not known whether the lack of increased expression of IL-17A in severe asthma is truly reflective of pathology, or is indicative of the effects of high-dose corticosteroids taken in these patients on the T17 pathway. Indeed, previous data show that systemic corticosteroids can reduce IL-17 expression [69]. Clinical trials of monoclonal antibodies that target IL-17 have yielded disappointing results [70]. Blocking IL-23 may hold greater promise as a treatment for T2LOW asthma as it is upstream of IL-17 in the inflammatory cascade, and phase II trials of anti-IL-23 treatment are in progress [47].

Although mixed T2 and T1/17 inflammation do not often occur together, and the patient population with a mixed granulocytic sputum profile is relatively small, they present a group whose asthma management remains a significant challenge. Interventions able to target both T2HIGH and T2LOW inflammation may be helpful in treating this group, although none are currently available.

As described above, genuine-isolated T2LOW inflammation may be much less common than currently thought. Most apparent T2LOW patients have an element of T2HIGH disease, which may be being masked by corticosteroid therapy. Therefore, it is important to consider that persistent symptoms in seemingly T2LOW corticosteroid-treated patients may be related to other asthma and non-asthma mechanisms and factors.

Airway hyperresponsiveness

AHR reflects increased/dysfunctional airway smooth muscle (ASM) contraction due to a range of direct or indirect stimuli. AHR is augmented by T2HIGH and T2LOW inflammation. Asthmatics who do not obviously exhibit either T2HIGH or T2LOW inflammatory profiles (i.e. paucigranulocytic profile in sputum) usually have less severe asthma and less frequent exacerbations. However, this group still have asthma characterized primarily by AHR, and may exhibit significant bronchospastic symptoms, even in the absence of detectable airways inflammation. It is therefore important to remember that AHR can be a feature in any asthmatic patient, regardless of their underlying inflammatory profile.

Mast-cell infiltration into the ASM is increased in asthma, when compared with both healthy controls and patients with eosinophilic bronchitis [71,72]. This contrast between asthma and eosinophilic bronchitis is important given that the degree of eosinophilic inflammation is similar in both conditions [71], with the presence or not of AHR being the important physiological difference between the two diseases. Degree of ASM mast cell infiltration also correlates with bronchial reactivity as measured by Methacholine PC20 [71]. Together these findings suggest that mast cells in ASM play a specific role in AHR, through release of mediators including histamine, PGD2 and cysteinyl leukotrienes, which can directly induce contraction of the ASM, with consequent AHR [71,72]. Mast cells located in the ASM bundle also release cytokines IL-4 and IL-13, which is not seen in health or in eosinophilic bronchitis, again suggesting that mast cells play a specific role in asthma and AHR that is not seen in eosinophilic bronchitis [73]. Mast cell development and survival are dependent on stem cell factor and its receptor KIT (KIT proto-oncogene receptor tyrosine kinase). Treatment with the KIT inhibitor Imatinib reduces airway hyperresponsiveness, mast cell numbers and tryptase levels (a marker of mast cell activation) in patients with severe asthma, adding further support to the relationship between mast cell activity and airway hyperresponsiveness [74]. However, the side effect profile of Imatinib may limit its potential as a treatment for asthma.Recruitment of mast cells to the ASM appears to be primarily mediated by CXCL10 expressed on ASM cells interacting with CXCR3 expressed on the surface of mast cells [72]. CXCL10 and CXCR3 show markedly increased expression in smooth muscle cells and mast cells located in the region of the ASM of asthmatics [72]. Mast cells located in the airway ASM also differentiate under the influence of ASM-derived extracellular matrix proteins to become fibroblastic, and the prevalence of such altered mast cells in the ASM is related to the degree of AHR [75].

Stimuli such as oxidative stress and inhaled environmental pollutants can also increase AHR. ASM exhibits increased responsivity in association with higher levels of oxidative stress related to increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) expression [76]. Epithelial-derived IL-33 also contributes towards maintenance of AHR during allergen challenge [49]. Damage of the airway also promotes release of nuclear-located high mobility group box-1 protein (HMGB1). This HMGB1 amplifies ASM hypercontractility via activation of Toll-like receptor-4 rather than the receptor for advanced glycation end-products (RAGE) [77].

Airway remodelling

Airway remodelling encompasses various structural changes in the airway including, epithelial changes, mucous-gland hyperplasia, thickening of the subepithelial collagen layer, increased submucosal matrix deposition, hypertrophy and hyperplasia of ASM, and mast cell localization and degranulation in the ASM bundle [76,78,79].

CT imaging diagnosed bronchial wall thickening and bronchiectasis are common in the severe asthma population [63]. Prevalence of bronchiectasis is significantly higher in severe asthmatics who smoke compared with those who do not, suggesting that environmental exposures in susceptible patients lead to a greater risk of developing airway wall changes such as bronchiectasis [63]. However, it is not possible to say definitively whether bronchiectasis is a part of the natural progression of severe asthma, or whether bronchiectasis in severe asthma instead reflects a separate co-morbid entity contributing to the difficulties in treatment [63].

Macro-level CT-derived measures of airway remodelling are associated with micro-level remodelling changes on bronchial biopsy samples. ASM mass and epithelial thickness measured on bronchial biopsies both predict cross-sectional bronchial luminal area and airway wall area on CT [80]. Therefore, increased ASM mass and epithelial thickness could account for some of the bronchial wall thickening seen on CT scans of severe asthmatics.

Bronchial biopsy samples from mild, moderate and severe asthmatics, and in health show that the degree of epithelial hyperplasia and metaplasia significantly increases in line with severity of asthma [44]. Changes in the structure and integrity of the epithelial barrier results in ciliary dysfunction, with reduced ciliary beat frequency and increased dyskinetic and immotile cilia [81]. Cilial dysfunction is associated with important clinical features such as impaired lung function and AHR, although not with sputum eosinophilia, suggesting it is not simply related to airways inflammation, but more likely the result of a complex of factors including exposure to inhaled irritants and bacterial infection [81]. Altered cilial function contributes to impaired sputum clearance from the airways and mucous plugging, which are features of severe asthma and often found in fatal asthma exacerbations. Epithelial damage also leads to reduced barrier function with a subsequent increase in susceptibility to inhaled pathogens, allergens and pollutants, which in turn triggers the inflammatory cascades presented above.

Bronchial thermoplasty is thought to treat some of the airway remodelling changes seen in severe asthma by the application of radiofrequency thermal energy to the airway wall during bronchoscopy. Small studies have shown reductions in ASM mass, reticular basement membrane thickness and collagen deposition following treatment [8285]. Larger trials have shown an improvement in asthma symptoms and reduction in exacerbation frequency, but no change in lung function to accompany the reduction seen in ASM mass [86].

Some recent studies of pharmacological therapies for asthma have examined the effect of treatment on airway remodelling. In vitro studies have shown that the presence of DP2 in asthmatic airways increases goblet cell formation and epithelial metaplasia [44]. Placebo-controlled clinical trial data also showed that 12 weeks of treatment with Fevipiprant (anti-DP2) significantly reduces ASM mass [87]. Mechanistically, this appears to be the result of the combined effects of reduced airway inflammation and a direct effect from Fevipiprant of the ASM itself [87]. The calcium channel blocker Gallopamil has also been shown to reduce ASM mass and reticular basement membrane thickness following 12 months of treatment within the treatment group, but differences were not observed between those treated with Gallopamil compared with placebo [88].

Dynamic mechanical forces on the lung, and in particular the airway epithelium, can cause significant inflammatory stress independent of the T2HIGH or T2LOW mechanisms described above. These forces originate from a range of actions including breathing (particularly deep inspiration), coughing and ASM contraction with bronchoconstriction [89]. Mechanical strain and compressive stress in vitro inhibit epithelial repair in response to injury, increase the release of pro-fibrotic cytokines such as transforming growth factor (TGF)-β2 and endothelin, increase production of reactive oxygen species (ROS) and resultant oxidative stress, and down-regulate prostaglandin E2 synthesis [89].

Extra-thoracic factors

A range of extra-thoracic factors can also influence and interact with asthma disease mechanisms. Asthma is often accompanied by allergic rhinitis (over 80% of asthmatics) and/or nasal polyps (4%) [90]. Atopy alone does not explain the association between asthma and allergic rhinitis as rhinitis is frequently seen in non-atopic asthmatics, and nasal symptoms are associated with more severe asthma in this group [90]. Even in the absence of asthma, patients with upper respiratory tract disease have evidence of lower airways inflammation and remodelling, although to a lesser degree than those with asthma [90]. This supports the concept of the upper and lower airways being intrinsically linked through a shared epithelium, and nasal challenge testing increases the presence of eosinophil progenitor cells in the bone marrow in the same way as lower airway stimulation [90]. However, some of the relationship between upper and lower airway disease may be as a consequence of physical factors, as rhinitis and polyps cause nasal congestion that leads to increased mouth breathing. This increases the exposure of the lower airways to allergens and pathogens, as mouth-inspired air has not been filtered by the nose [90].

Asthmatics who are obese often present as a specific phenotype, with a lesser degree of eosinophilic inflammation and reduced sensitivity to corticosteroid therapy [7]. Although the mechanisms are not entirely understood, obesity may influence asthma through numerous factors including mechanical (such as extra-thoracic lung volume restriction), genetic, inflammatory (such as increased inflammatory cytokines/proteins associated with obesity and the metabolic syndrome) or related to co-morbidities associated with obesity (such as obstructive sleep apnoea and gastro-oesophageal reflux disease) [90,91]. Regardless of mechanism, weight loss improves asthma symptoms, exacerbation rates and lung function [90].

Smoking is common among asthmatics with up to 50% of asthmatics in Western Countries being current or former smokers [92]. Asthmatics who smoke have an increased burden of symptoms, and a higher risk of asthma exacerbation [92]. Smoking asthmatics have an attenuated response to corticosteroids, possibly related to increased neutrophilic airway inflammation, increased oxidative stress and altered glucocorticoid receptor balance associated with smoking [92]. Cessation of smoking reduces sputum neutrophil levels in non-eosinophilic asthmatics, and may subsequently lead to improved corticosteroid sensitivity [64]. Smoke exposure in non-asthmatics is associated with increased levels of eosinophils, macrophages and CD8+ lymphocytes and mast cells in the airways, as well as pro-inflammatory mediators such as IL-8 [92]. However, in the asthmatic airway, where an altered inflammatory profile already exists, the effect of smoke exposure is less clear. Studies have identified contrasting changes in the airway inflammatory profile in smoking asthmatics, although some of these differences could be accounted for by variations in study design and population [92]. There is even some evidence in rats to suggest that smoking may suppress eosinophilic inflammation; however, the mechanism for this is poorly understood [92]. Smoking also has airway remodelling effects, with epithelial hyperplasia and increased goblet cells seen in the airways of smoking asthmatics, although these changes appear to be mostly reversible following cessation of smoking [92].

Summary

The pathogenesis of asthma is complex, involves a multitude of interacting pathways, and our understanding of it remains incomplete. Here, we have described the most salient elements underpinning four key factors in asthma: T2HIGH inflammation, T2LOW inflammation, AHR and airway remodelling, and discussed additional factors that can influence an individual’s asthma such as genetics and co-morbidities.

The depth of our current understanding of asthma pathogenesis has allowed a range of new, targeted treatment options to be developed and begins to offer opportunities for a precision medicine approach to the individual patient. At present, the overlaps in our understanding of different endotype groups and the varied effects of therapy remain significant, but future progress in unpicking asthma pathogenesis will hopefully bring some clarity to these blurred lines. In addition, a significant proportion of our current knowledge originates from animal and in vitro models, and needs validation with in vivo human studies.

With the growth of biomarkers and a more detailed understanding of endotype profiles, it should hopefully soon be possible to evaluate an individual patients’ disease mechanism in great depth and tailor their treatment to that which will give the most clinical benefit. This is critical in developing future precision medicine strategies for asthma in a bid to reduce the burden of the disease to healthcare providers, and most importantly, to our patients.

Competing Interests

CEB has received grants or consultancy paid to his Institution from AZ/Medimmune, GSK, Chiesi, Novartis, Regeneron, Sanofi, Gilead, Glenmark, TEVA, BI, Roche/Genentech and Pfizer.

Abbreviations

     
  • AHR

    airway hyperresponsiveness

  •  
  • ASM

    airway smooth muscle

  •  
  • CRTH2

    chemoattractant receptor-homologous molecule expressed on Th2 cells

  •  
  • DP2

    D prostanoid receptor 2

  •  
  • GM-CSF

    granulocyte monocyte colony-stimulating factor

  •  
  • HMGB1

    high mobility group box-1 protein

  •  
  • IL

    interleukin

  •  
  • ILC2

    innate lymphoid type 2 cell

  •  
  • MBP

    major basic protein

  •  
  • PGD2

    prostaglandin D2

  •  
  • SNP

    single-nucleotide polymorphism

  •  
  • TGF-β2

    transforming growth factor-β2

  •  
  • TSLP

    thymic stromal lymphopoietin

  •  
  • VCAM-1

    vascular cell adhesion molecule-1

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