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Keywords:

  • Allergic inflammation;
  • asthma;
  • history;
  • stratified medicine;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

Eur J Clin Invest 2011; 41 (12): 1339–1352

Abstract

Background  Asthma is a disorder of the conducting airways that contract too easily and too much to cause variable airflow obstruction with symptoms of wheeze, cough, chest tightness and shortness of breath. Based on this knowledge, initial treatments were directed to dilating the contracted airways with anticholinergic and adrenergic drugs. The recognition that allergic-type inflammation underlay the hyperresponsive airways in asthma led to the introduction of anti-inflammatory drugs such as sodium cromoglicate and corticosteroids. Over the 2 decades that followed, these drugs have been progressively improved by increasing their therapeutic index and duration of action.

Methods  A review of the recent literature indicates that since the 1980s, the explosive increase in knowledge of the cell and mediator mechanisms of asthma has only led to modest improvements in therapy including the introduction of leukotriene modifiers and a blocking monoclonal antibody against IgE. Indeed, biologics targeting allergic cytokines and effector cells have on the whole proven disappointing despite initial promise being shown in animal models.

Results  Part of the difficulty lies in the oversimplified concept that asthma is only driven by allergic processes when in reality there are many environmental causes and triggers and the view that it is a homogeneous disorder only varying in severity.

Conclusions  The more recent views that asthma is a complex disorder made up of different subtypes with differing causes, treatment responses and natural histories creates a new opportunity for stratified medicine in which therapies acting upstream selectively target specific disease subtypes identified by specific diagnostic biomarkers.


Asthma: an historical perspective

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

The term ‘asthma’ was derived from the Greek word for shortness of breath, which encompassed many clinical conditions of the heart and lungs. It was not until the mid-nineteenth century that the term became more restricted to the disease of variable airflow obstruction following the careful clinical and physiological observations of Dr Henry Hyde Salter made on 50 patients he had collected in London and published in his treatise On Asthma and its Treatment (1860) [1]. It was Salter who defined asthma with remarkable insight as ‘Paroxysmal dyspnoea of a peculiar character with intervals of healthy respiration between attacks’, recognised that these episodes were caused by contraction of smooth muscle that differentiated it from ‘bronchial catarrh, recent bronchitis and old bronchitis’ and that there were unusual cellular elements in asthmatic sputum some 30 years before Paul Erhlich discovered aniline dyes for histochemical staining [2]. Osler also observed that he could help his patients with asthma by suggesting them to take strong black coffee (containing the bronchodilator xanthines, theophylline and theobromine). Thus, by the late nineteenth century, physicians believed that asthma was a disease that had a specific set of causes, clinical consequences and requirements for treatment. However, it was William Osler, the pioneer of scientifically based medicine, whom, as with so many other diseases, combined clinical observation, physiology and pathology to capture the principle elements of asthma in his first issue of his textbook Principles and Practice of Medicine first published in 1860 [3].

Description of asthma by William Osler

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References
  • 1
     Spasm of the bronchial muscles.
  • 2
     Swelling of the bronchial mucous membrane.
  • 3
     A special form of inflammation of the smaller bronchioles [bronchiolitis exudative: (Curschmann)].
  • 4
     Hay fever has many resemblances to asthma.
  • 5
     The affection runs in families.
  • 6
     The disease often begins in childhood and sometimes lasts into old age.
  • 7
     Bizarre and extraordinary variety of circumstances that at times induce a paroxysm:
    • (a)
       Climate and atmosphere e.g. hay, dust and cat.
    • (b)
       Fright or violent emotion.
    • (c)
       Diet (overloading of the stomach) or certain foods.
    • (d)
       Cold infection.
  • 8
     Sputum is distinctive: rounded gelatinous masses (‘perles’) and Curschmann spirals and octahedral crystals (Leyden).

Throughout the nineteenth century, the only specific treatment for asthma was inhalation of the smoke from the Indian herb, Datura strammonium [4] (Fig. 1). This was burnt in pipes or cigarettes (asthma cigarettes), the inhaled smoke containing an atropine-like alkaloid that had some bronchodilator actions. Asthma cigarettes were available up to the late 1960s, but whether their long-term use caused more harm than good is debatable. However, in 1901, it was the discovery of adrenaline that opened the door for effective bronchodilator therapy. Adrenaline was initially administered by injection, but later as an aqueous aerosol from a hand-operated spray. Refinement of the catechol ring of adrenaline in 1947 led to discovery of isoprenaline (isopreterenol) in which the alpha-adrenergic activity was removed to create a beta receptor-selective agonist [5] (Fig. 1). Isoprenaline was also made available in a pressurised metered dose formulation using CFCs as propellant. These were a great success and confidence increased with high-dose preparations becoming available as over-the-counter preparations. However, increased asthma mortality in countries where the isoforte preparations were available (UK, Australia and New Zealand) led to the removal of the isoforte preparation and isoprenaline-metered dose inhalers only being available by prescription. There was considerable debate at the time over the mechanisms involved that increased the risk of death that varied from β-receptor tolerance to cardiac muscle sensitisation by high levels of circulating chlorinated fluorocarbons (CFCs) in the presence of hypoxia during a severe asthma attack [6].

image

Figure 1.  Evolution of bronchodilator therapies for asthma starting with the anticholinergic treatment from the herb Datura strammonium, the discovery of adrenaline to refinement of adrenergic drugs both with respect to selectivity for G protein-coupled receptor (GPCR) subtypes and duration of action (short- and long-acting β2-agonists: SABA and LABA).

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The peak of asthma deaths, recognised by Doll and Speight, also stimulated further chemical modification of the adrenergic bronchodilators with the catechol ring being replaced with a saligenen ring and further modifications to the carbon side chain leading to the discovery of salbutamol by David Jack in 1968 [7] (Fig. 1). The pharmacology behind this was predicated on separating β2 (bronchodilator) from β1 (chronotropic/inotropic) receptor activity in favour of the former. A series of short-acting bronchodilators followed including terbutaline, rimiterol and fenoterol. However, a second peak in asthma mortality peaking in the mid-1980s once again raised concerns over the safety of the short-acting bronchodilators, which led to restrictions being imposed on their use and over-use during severe exacerbations, especially in the case of fenoterol in New Zealand, where once again a high-dose formulation was available [8]. It was during this period that some of the first asthma guidelines were developed discouraging widespread reliance on inhaled bronchodilators in favour of greater use of anti-inflammatory controller drugs.

More recently, further chemical manipulation of the β2-adrenoceptor agonist backbone and ring led to the discovery of long-acting drugs (LABAs) such as salmeterol and formoterol [9]. As with short-acting β2-agonists, controversy has arisen over their possible link to excess asthma mortality for reasons that are far from clear [10]. It is stated that this serious adverse effect does occur when LABAs are combined with an inhaled corticosteroid, but this remains to be proven beyond reasonable doubt [11]. Until this time, LABAs are subject to intense pharmaco-surveillance. This will be especially important because very long-acting β2-agonists are currently in clinical trial and where any such risk might be greater than that of LABAs.

Throughout the second half of the twentieth century, injectable aminophylline and oral theophylline (both standard and slow release) were used as bronchodilators the former in the acute asthma setting as emergency treatment and the latter as a maintenance therapy [12]. While undoubtedly successful, these methylxanthines were accompanied by appreciable side effects (cardiac arrhythmia, nausea and vomiting, convulsions and diuresis) that, despite the introduction of serum drug level monitoring, were eventually surpassed by alternative approaches to asthma control.

Thus, by the early–mid-1960s, asthma was still regarded as a disease of episodic bronchospasm treated with inhaled bronchodilators and systemic xanthines. At the turn of the twentieth century the discovery of cortisone as a hormone possessing both mineralocorticoid and glucocorticoid activity, with the latter dominating, led to its synthesis and use as an anti-inflammatory drug in inflammatory joint diseases, especially rheumatoid arthritis, the first convincing studies being conducted by PA Hench at the Mayo Clinic in 1947 [13]. The dramatic suppressive effect on inflamed joints was soon apparent, but because the drug was given orally or by injection bone-destructive side effects soon became apparent. In the case of asthma, cortisone or hydrocortisone were also shown to be highly efficacious in treating exacerbations of asthma as well as in preventing acute attacks [14]. However, in the latter case, it was possible to administer the treatment directly to the airways by inhalation. It was this concept of reducing systemic exposure and at the same time increasing drug concentration within the airways that led to the development of beclomethasone dipropionate (BDP) for inhalation. The work was lead by the British pharmaceutical company Allen and Handburys and culminated in a range of different BDP metred dose inhalers (MDIs) that could be used twice daily in accordance with asthma severity [15]. It was soon shown that both oral and inhaled corticosteroids suppressed airway inflammation with dramatic effects in stabilising the variable airflow obstruction that characterised active asthma [16]. By controlling asthma, regular inhaled corticosteroids became the mainstay of asthma treatment. For the majority of patients with asthma, a combination of inhaled corticosteroids as the controller and inhaled bronchodilators as the reliever results in the majority of mild–moderate asthma being controlled. What is left is the 10% or so who have severe difficult-to-treat disease in whom the direct and indirect health costs are greatest. It is these patients that more attention needs focusing upon.

Asthma mechanisms: early concepts

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

By the early 1970s, our therapeutic options for asthma were widening. However, more was to follow. The demonstration that mast cells were prime effecter cells of allergen-induced bronchoconstriction and were also activated to release their mediators in asthma provoked by other exogenous stimuli such as exercise, cold air and fog placed these cells as the gatekeepers of the acute asthmatic response. While Dale and Laidlaw [17] had already described histamine as a potent anaphylactic mediator, it was not until 1921 that Prausnitz and Küstner identified reagin as a substance that could passively transfer a positive allergen skin-prick reaction from a sensitised allergic subject to a nonallergic individual [18].

It took a further 47 years before reagin was shown by Kimishiga Ishizaka (Denver, Co, USA) and Gunnar Johansson (Uppsala, Sweden) to be the fifth immunoglobulin class, IgE [19]. This knowledge, together with an understanding that allergens could crosslink IgE on the surface of mast cells and basophils to release histamine and other inflammatory mediators, provided a firm basis for how allergic reactions were initiated. One year earlier, the first randomised control clinical trial of the anti-allergic drug, sodium cromoglycate, now spelt cromoglicate (SCG) was published [20]. This bis-chromone was discovered by Roger Altounyan while investigating the anti-allergic properties of khellin extracted from a herb, Ammi visnaga, from Armenia that inhibited IgE-dependent histamine release from rodent mast cells in vitro [21] (Fig. 2). Sodium cromoglicate was administered as a dry powder from a Spinhaler® device and was highly effective at blocking both allergen-induced and exercise-provoked asthma [22]. It was widely used as a controller therapy in allergic asthma especially in children on account of its negligible side effects and its ability to inhibit both allergen- and exercise-provoked asthma [23]. Unfortunately, this drug is now no longer available on the WHO list of drugs following a meta-analysis of selected clinical trials [24], a decision that has been vigorously challenged [25]. It could be said that this was a drug born before its time because it was known to be highly effective in certain but not all patients with asthma, and yet identifying responders from nonresponders was the problem. I shall return to this issue later in this review.

image

Figure 2.  The discovery of sodium cromoglicate by Roger Altounyan and the establishment of the pharmaceutical company Fisons. Roger spent his childhood holidays with Arthur Ransom’s family in the Lake District in the UK and features as the Roger in the children’s book ‘Swallows and Amazons’. Dr Altounyan extracted Khellin from a herb (Ammi visnaga) his father brought back from Armenia that was used there to treat chest problems. Sodium cromoglicate was a bis-chromone synthesised from khellin and administered to patients with asthma as an inhaled dry powder via a Spinhaler device. Sodium cromoglicate is a mast cell stabiliser.

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During the period in the 1960s when SCG was being developed, Jack Pepys [26] described allergic responses in two phases: early and late. The early phase following allergen provocation resulted from the local actions of mast cell mediators such as histamine, prostanoids, heparin and slow-reacting substance of anaphylaxis (SRS-A, later to be identified as suphidopeptide leukotrienes). The late phase was thought to result from an influx of inflammatory leucocytes especially eosinophils with a second wave of mediator release. Prior to this period, the eosinophil was considered to be a protective cell whose job it was to inactivate mast cell–derived mediators such as histamine, heparin and SRS-A [27]. However, during the 1980s the eosinophil was placed as the central pro-inflammatory cell of asthma and other more chronic allergic disorders. It was shown to release a range of highly basic granule-associated proteins: major basic protein, eosinophil cationic protein and eosinophil-derived neurotoxin [28]. This period of asthma research also linked activated T lymphocytes to the recruitment of eosinophils with factors such as eosinophil chemotactic factor of anaphylaxis (ECF-A) and eosinophil-activating factor (EAF) [27,29] (Fig. 3). These factors were described in terms of their biological activities in the absence of structural identification. A range of other factors were identified for other inflammatory cells associated with the late-phase allergic response such as platelet-activating factor (PAF, to be later identified as an ether phospholipid [30]), high-molecular weight neutrophil chemotactic factor (HMW-NCF), lymphocyte inhibitory factor (LIF), macrophage/monocyte-activating and inhibitory factors (MAF and MIF), etc. [31]. PAF was subsequently identified as a strong candidate therapeutic target for asthma, but despite the synthesis of selective receptor antagonists (that included the anti-histamine, ketotifen) being shown to be active in a range of animal models of allergic inflammation, they universally failed when assessed by clinical trial in human asthma and were eventually dropped from further development [32].

image

Figure 3.  The conceptual basis of allergic diseases such as asthma beginning with the opposing functions of mast cells and eosinophils in the 1960s, through to the identification of T lymphocytes as orchestrators of allergic inflammation in the 1970s, the partitioning of T cells into the Th1 and Th2 subtypes, the latter being linked to allergic inflammation and parasite immunity to the current understanding of multiple T-cell subsets including those that regulate Th2 responses (Treg cells) and others that drive Th-2 responses (Th17 cells).

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Redefining immunological pathways in asthma

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

A major breakthrough occurred in the early 1990s with the discovery of cytokines as a large family of small proteins and peptides that provided the structural basis for the various leucocyte ‘factors’ [33]. The description by Mosmann of two types of T lymphocyte based on their cytokine repertoire and linked functionally to different immune responses, Th1 (IFN-γ and IL-2; antimicrobial defence, autoimmunity) and Th2 (IL-4, -5, -9 and -13; allergy and parasite defence) suddenly opened up the entire immunological field of asthma and associated allergic disorders. This new knowledge enabled detailed dissection of immunological processes linked to the initiation and perpetuation of allergic-type tissue responses (Fig. 3). Although the T cell had been incriminated in orchestrating the allergic inflammatory response since the early 1980s, understanding that there were selective cytokines emanating from a particular subset of T cells provided a clearer understanding of how allergen exposure in atopic subjects could initiate both an IgE and a specific effector cell response involving mast cells, basophils and eosinophils [34]. The key to this initiating set of signals was the recognition, uptake, processing and subsequent MHC class II restricted presentation of allergenic epitopes by professional antigen-presenting cells (dendritic cells, DCs). This along with engagement of co-stimulatory molecules on T cells lead to their differentiation into a Th2 subtype [35]. Subsequent exposure to the same allergen epitopes stimulated the secretion of the Th2 cytokines through the coordinate activation of a cluster of cytokine genes encoding IL-3, IL-4, IL-5, IL-9, IL-13 and GM-CSF on chromosome 5q31-33. The identification of chemokines more or less selective for the allergic effector cells that included the eotaxins (1–3), TARC, MDC, RANTES and MCP 1-3 (CCL17, 22, 5, 2, 8 and 7, respectively) [36] provided the necessary link between T-cell activation and the chemoattraction of effector leucocytes engaged by adhesion molecules whose expression was enhanced by released mast cell, macrophage and T cell mediators interacting with the microvascular endothelium [37].

Therapeutics emerging from mechanistic asthma research

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

Thus, by the mid-2000s, a pretty comprehensive picture of the allergic cascade had been described. Moreover, the cellular and mediator targets for these drugs were reasonably well established. The last 10 years has witnessed some further embellishment of these pathways with discovery of further cytokines such as the IL-17 family (especially IL-17 A, E (IL-25) and F), IL-33, IL-35 and thymic stromal lymphopoietin (TSLP), to name but a few. These cytokines orchestrate Th2 and Th17 immunological responses [38] (Fig. 4).

image

Figure 4.  Schematic representation of the interacting immune, inflammatory and structural cells involved in the asthmatic process. Reproduced with permission from Macmillan Publishers Ltd: Nature, Galli SJ, Tsai M, Piliponsky AM, The development of allergic inflammation, 454:445–54. Copyright 2008 {Ref. [38]}.

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With this tremendous increase in knowledge of the allergic pathways of asthmatic inflammation, it is now timely to ask whether any new therapies have emerged or are on the horizon as a result. The discovery by Samuelsson et al. [39] of leukotriene B4 as the novel neutrophils chemoattractant generated from arachidonic acid and the subsequent identification of cysteinyl leukotrienes (C4, D4 and E4) as the constituents of SRS-A. This discovery led to the development of selective receptor antagonists such as montelukast, zafirlukast and pranlukast [40]. However, it should be noted that SRS was first described as a possible mediator of asthma by Kellaway and Trethewie as far back as 1938 [41], but it took a further 40 years before its molecular basis was clearly understood with many false starts. The more recent discovery of the Cyst LTr1 as the receptor that mediates the smooth muscle, vascular, mucous, secretory and neural aspects of LTC4 and LTD4 as well as activating both monocyte/macrophages and eosinophils provided a rational explanation for why blockade of this mediator class is of benefit in asthma. The discovery of two further receptors, Cyst LTr2 and Cyst LTr3 (more selective for LTE4), has broadened the interest in leukotriene biology, especially in relation to airway wall remodelling and fibrosis in chronic asthma [42]. In the long term, it might be more beneficial to inhibit Cyst LT production via 5-lipoxygenase (5-LO) as achieved with zileuton (but with reduced off target liver side effects) rather than picking off one receptor at a time. Unfortunately, despite a number of trials of other 5-LO inhibitors, none have so far made it to the clinic [43]. The great advantage of leukotriene modifiers is that they can be administered orally rather than by inhalation. A distinct disadvantage on account of the selectivity of the target (cyst LTR1) is that there exist responders and nonresponders that may in part be genetically determined [44].

The only other novel therapy to emerge in recent years is omalizumab, a humanised monoclonal antibody that binds to that part of the Fc region of IgE that serves as the binding site for both the high-affinity (FcεR1) and low-affinity (FcεR2, CD23) receptors [45]. The small tri- and hexameric immune complexes formed are rapidly removed without effect and following injection, free IgE in the circulation falls dramatically. The net result over several weeks is the removal of IgE from mast cells, basophils and DCs (dendritic cells) with subsequent internalisation of their FcεR1 receptors. By interrupting the trigger mechanism for the allergic cascade, omalizumab is anti-inflammatory [46]. Clinical trials established its efficacy in severe corticosteroid-requiring allergic asthma. Its expense as well as being an injected medication limits its use to the very severe end of the asthma spectrum [47]. It is administered in a dose commensurate with the total serum IgE level and body weight. Clinical efficacy is assessed at 16 weeks because there are responders and nonresponders that cannot be distinguished at baseline and only by a full physician’s assessment after therapy for 16 weeks. One advantage of omalizumab is its ability to block allergic pathways distant from the lung and is also therefore effective against allergic co-morbidities that so often occur in severe asthma such as rhinitis and urticaria [48].

The discovery of a selected range of cytokines associated with the allergic cascade has made them attractive therapeutic targets. Beginning with IL-4 and IL-9, a wide range of biologics have been trialled in severe asthma without broad efficacy yet being shown [49]. This disappointing outcome also extends to IL-5, the cytokine responsible for maturation of eosinophils and their survival. Mepolizumab is a monoclonal IgG antibody directed to IL-5 with dramatic effects in reducing circulating and lung eosinophils in primate ‘models’ of allergic airway disease [50]. Two subsequent studies, one targeting the allergen-induced late-phase airway response [51] and the other a large clinical trial in moderate–severe asthma [52] have both failed clinically despite dramatic effects in reducing sputum and circulating eosinophils. A subsequent bronchial biopsy study showed that the airway tissue eosinophil content was only reduced by ∼50%, whereas the sputum and blood eosinophils were depleted by > 80% [53]. These disappointing results were surprising especially because mepolizumab was so effective in other eosinophilic disorders such as eosinophilic oesophagitis and some forms of hypereosinophilic syndrome [54]. It was suggested that its lack of effect in asthma was the consequence of ∼50% of tissue eosinophils in asthma losing their IL5rs and therefore losing their ability to respond to IL-5 [55]. More recently, two further trials of mepolizumab in very severe oral corticosteroid-requiring patients with asthma with persistent sputum eosinophilia (∼0·1% of the asthmatic population) have shown efficacy in reducing asthma exacerbations by 50–80% [56,57]. Again, this identifies the issue of responders and nonresponders, this time identified by a requirement for high-dose corticosteroids and persistent sputum eosinophilia.

Interleukin 13 has also been a target that has attracted much attention in asthma. This molecule shares with the IL-4r the IL4rα chain [58]. High-profile publications in the 1990s placed IL-13 at the centre of the asthmagenic cytokines because not only was it capable of generating prolonged IgE isotype switching in B cells and enhanced mast cell and eosinophil functions but also is implicated in mucus production, fibrosis and smooth muscle cell proliferation and maturation. Furthermore, animal models in which this molecule or its receptors were deleted or blocked (mostly in mice) exhibited marked reductions in airway allergic inflammatory responses as well as in aspects of airway wall remodelling [59]. A large number of humanised or human blocking monoclonal antibodies against IL-13 or the shared IL4rα have been developed (at least 15 in the pipeline at the time of writing). However, the initial positive results obtained with an IL-4 double mutein (pitrakinra, inhaled and injected – Aerovance) [60] (that acts as a receptor antagonist) and the monoclonal anti-Il-13 antibody (IMA-638, Wyeth now Pfizer) in allergen challenge showing an attenuated late-phase reaction, have not yet translated to clinical efficacy in asthma trials in moderate–severe disease. Another monoclonal antibody directed to the common IL4rα (AMG-317; Amgen, Thousand Oaks, CA, USA) has also been tested in a 12-week clinical trial at three doses and also found to be ineffective despite showing evidence for reducing circulating IgE levels and eosinophils [61]. In the upper one-third of disease severity, there was a hint of efficacy, but small numbers resulted in no significant change in measured asthma outcomes.

Overall, these disappointing clinical results could still be explained on the basis of inadequate evidence for involvement of IL-13 as a functionally important cytokine in the human disease asthma (as opposed to animal models of allergic-type inflammation). Indeed, a January 2010 literature review of PubMed for IL-13 identified almost 3000 peer-reviewed publications on its potential role as a key cytokine in allergic and parasitic diseases, but by the time the search was limited to human asthma and direct evidence, the number dropped to six that included two reviews! Two of the four publications came from a single laboratory in the UK [62,63], demonstrating the increased presence of IL-13 in sputum in ∼50% of patients, with little or no link to disease severity. Thus, a clinical trial based on a target that is only expressed in half the patients with asthma is destined to be negative (50% responders and 50% nonresponders).

Further insight into the anti-IL13 responder/nonresponder issue has been provided by an attempt to subphenotype IL-13+ asthma from those not expressing or utilising this cytokine as part of their disease pathobiology. Using epithelial brushings, Woodruff et al. [64] has shown that multiple gene expression revealed two distinct subgroups: ‘Th2-high’ (many IL-13+ genes expressed) and ‘Th2-low’ asthma (the latter indistinguishable from control subjects) with approximately half of patients falling into each group. Interestingly, the two subgroups differed in their expression of IL-5 and IL-13 in bronchial biopsies and airway hyperresponsiveness, serum IgE, blood and airway eosinophilia, subepithelial fibrosis (as a marker of epithelial injury) and airway mucin gene expression. The lung function improvements expected with inhaled corticosteroids were restricted to the ‘Th2-high’ asthma. They concluded that asthma could be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation. Furthermore, current models did not adequately explain non-Th2-driven asthma, which represents a significant proportion of patients and responds poorly to current therapy. Although bronchial brushing to obtain a transcriptomic fingerprint is not practical, this study does illustrate the potential for identifying biomarkers in relevant pathways that impact on therapeutic responses.

The sentinel role of the eosinophils as the primary inflammatory effector cell of tissue damage in asthma is once again being challenged. Lee et al. [65] suggest that accumulating tissue eosinophils serve as regulators of local immunity and/or remodelling/repair (the LIAR hypothesis). As part of this new concept, it is suggested that eosinophils initiate an expansion of regulatory T cells, and in doing so may function to quell subsequent allergen-driven responses [66] Hence, the eosinophils is again being repositioned as a protective rather than a cytotoxic cell as was its position in the allergic cascade 50 years ago [27].

Another cytokine that has attracted some attention in severe asthma is TNFα. blockade of TNFα has been of major significance for the treatment of other chronic inflammatory disorders such as rheumatoid arthritis, psoriasis, inflammatory bowel disease and sarcoidosis [67]. There has accumulated substantial evidence in severe corticosteroid refractory asthma that TNFα is a key candidate mediator. Three small clinical trials using the TNFr1 fusion protein, etanercept, suggested efficacy with a particular effect against airway hyperresponsiveness [68–70]. The study by Berry et al. [69] also identified that the expression of TNF and its receptors on circulating mononuclear cells was a useful indicator for efficacy. Subsequently, a large multi-dose clinical trial of the anti-TNFα monoclonal antibody golimumab (Centocor) over 26 weeks, failed to confirm efficacy [71]. However, in subgroup analyses those patients with more reversible airflow obstruction and upper airway co-morbidity did respond in a dose-dependent manner. Unfortunately, severe adverse effects that included infection and cancer stopped further exploration of this.

With these somewhat disappointing results in targeting cytokines or their receptors, there have been attempts to block T-cell activity. While small trials of cytotoxic and immunosuppressant drugs (methotrexate, azathioprine, gold, tacrolimus and cyclosporine) indicated efficacy in some patients, side effects proved a real problem [72]. Biologics have also been used including anti-CD4 [73], anti-CD25 (IL2rα) [74] and anti-CD23 [75] and, while some patients showed evidence of a response, others did not or else the overall response was too weak to continue development. Again, a disappointing outcome considering the proposed sentinel role of T cells in prevailing hypotheses of asthma pathogenesis. Finally, both in primary and secondary prevention, allergen avoidance has proven disappointing when single avoidance strategies are used, but combination approaches look more promising at least in milder disease with a strong allergic component [76]. Similarly, allergen immunotherapy using subcutaneous or sublingual allergens, while helpful in mild asthma associated with rhinitis, seems far less effective in more severe disease where there is also concern over anaphylactic side effects [77].

Time to change asthma paradigms: a forward look

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

After these overall negative results and against a background of strong underpinning science, it is legitimate to ask whether the overall hypothesis for asthma pathogenesis is correct. It is clear that for mild–moderate asthma, IHC with or without LBAS and/or LTRAs are sufficient to control asthma, but this does not represent a cure. In addition, the outstanding unmet need is severe poorly controlled asthma where current therapies fail. What has been missing in much of the mechanistic underpinning science in vitro or in animal model systems is an understanding of the chronic nature of asthma, the importance of smooth muscle changes that define the human disease, the wide range of environmental factors beyond allergen exposure that drive the inception, exacerbation and persistence of asthma and lack of consideration of the airway context where these immunological and inflammatory reactions occur [77,78,79]. Simple allergen sensitisation and challenge in animals fall a long way short of real asthma as experienced by patients [80]. Indeed, the only animal that experiences naturally occurring asthma is the cat [81], and yet this has never been explored as a potential model system. Apart from improved animal models that more closely reflect the human disease, greater attention needs to be given to the developmental origins of asthma, subphenotyping the disease and how different environmental factors interplay in disease pathogenesis.

Recent research suggests a key role for respiratory viruses (especially rhinoviruses) as an initiating factor that sets the airways in a state where sensitisation to allergens is more likely [82,83]. Here and with other environmental influences (pollutants, environmental tobacco smoke, drugs, etc.) the airway epithelium seems to be of particular relevance because this structure serves as a physical, metabolic and innate immunological barrier that is strongly influenced by all these factors. Because DCs are in intimate contact with the epithelium, it seems highly likely that epithelial cells play a particular role in their programming as suggested recently [84].

The epithelium in severe asthma has long been known to be abnormal as evidenced by the presence of increased numbers of epithelial cells in bronchoalveolar lavage and sputum (Creola bodies). The presence of increased expression of growth factor receptors (e.g. EGFR) and their ligands by airway epithelial cells both in adult [85–88] and childhood asthma [89] in proportion to disease severity suggests that the epithelium is behaving like a chronic wound with increased susceptibility to injury and incomplete repair. Impaired epithelial repair follows from cell cycle arrest as suggested by the increased expression and nuclear translocation of such cell cycle inhibitors as P21waf and reduced epithelial proliferation markers: Ki67 and PCNA [89,90]. Recently, epithelial cell monolayers cultured from children with asthma have been shown to exhibit slower and incomplete repair responses following physical injury indicative of an intrinsic defect [91,92]. There is also evidence that the airway epithelium in asthma is more susceptible to oxidant-induced apoptosis with increased activation of the caspase enzyme cascade and accumulation of cleavage products such as the P85 product of 3′,5′-poly-ADP ribose polymerase (PARP) [93,94]. Indeed, in asthma there are numerous genetic studies suggesting impaired anti-oxidant defences that include loss-of-function polymorphisms [95].

Another characteristic feature of asthma is loss of integrity of the epithelial tight junction (TJ) complexes that renders it more permeable to environment insults including allergens, pollutants and micro-organisms [96,97]. These changes have been observed both in intact airway biopsies and in epithelial cells from asthmatic airways that have been cultured in vitro and differentiated at an air–liquid interface. Both transepithelial resistance and TJ integrity can be restored to asthmatic epithelium in vitro in the presence of exogenous epidermal growth factor (EGF) or keratinocyrte growth factor (KGF) possibly through regulating the expression and mobilisation of TJ claudins [98–100] linking this to the chronic wound scenario referred to above.

Asthma as a chronic wound of the conducting airways

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

As asthma becomes more severe and chronic, it tends to become less dependent on allergen-driven mechanisms. This might explain that, in anything but the mildest asthma, allergen reduction strategies have on the whole not been as helpful as might have been expected and also why in moderate–severe disease allergen-specific immunotherapy has been disappointing. The exception is occupational asthma where removal from the offending sensitising agent results in marked clinical improvement, but only if this is carried out early in the course of the disease. There is also mounting evidence that some occupational sensitisers such as di-isocyanates first damage the epithelium before evoking antigen-specific sensitisation after hapten formation [101,102]. Indeed, genetic polymorphisms of CTNNA3 (catenin alpha 3, alpha-T catenin) have been shown to be significantly associated with the TDI-induced asthma phenotype [103] and auto-antibodies to epithelial cell–derived cytokeratin 19 have been shown in TDI asthma [104].

Chronic epithelial damage leads to repair by ‘secondary intention’ involving the laying down of matrix and other features of remodelling. As in other chronic inflammatory disorders, remodelling involves a complex series of structural changes that includes proliferation of micro-vessels, new nerve networks in addition to the deposition of repair collagens and proteoglycans that together lead to thickening of the entire airway wall [105]. Severe asthma is also characterised by an increase in smooth muscle cells as well as increased collagen deposition and fibroblast/myofibroblast activity surrounding the smooth muscle bundles [106]. Mast cell infiltration of smooth muscle is also a characteristic feature of severe asthma [107]. That these mast cells evoke an autocrine secretion of TGFβ1 might explain the differentiation trajectory of mesenchymal stem cells towards smooth muscle cells [108]. Taken together, these observations suggest that the epithelium itself has embedded within it the origins and natural history of the different asthma phenotypes. An epithelium that is more susceptible to injury and displays impaired repair responses when injured creates a microenvironment enriched in cytokines and chemokines that could support a chronic inflammatory response as well as generating growth factors to drive airway wall remodelling [109] (Fig. 6). Such a paradigm has recently been tested in mouse models where EGF-driven responses are accompanied by remodelled airways, and manipulation of selective transcription factors such as reduced thyroid transcription factor 1 leads to both remodelled airways and goblet cell metaplasia as well as Th2-mediated inflammation [110,111].

image

Figure 6.  Schematic representation of disordered epithelial injury and repair in asthma that creates the micro-environment for sustaining inflammation and stimulating airway wall remodelling involving persistent activation of the epithelial mesenchymal trophic unit.

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The significance of airway wall thickening

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

The importance of the airway smooth muscle, vascular bed and neural networks has been underplayed in chronic asthma. These structures all contribute to the development of the foetal airways and are programmed to interact closely with the epithelium as the epithelial mesenchymal trophic unit (EMTU) in foetal branching morphogenesis. We have proposed that the EMTU becomes chronically reactivated in asthma and that this leads to a microenvironment that supports the chronic inflammatory response and airway wall thickening (Fig. 5). HRCT [112,113] as well as endobronchial ultrasound [114] has confirmed the importance of progressive airway wall thickening in more severe asthma. Although not intuitive, BHR assessed by bronchial provocation testing decreases in proportion to airway wall thickening [114,115]. Studies both in vivo and in vitro have confirmed that a damaged airway epithelium is a potent source of profibrogenic growth factors (FGFs, IGFs, EGFs, TGFβ/activin family), NGFs and VGFs (reviewed in [116]). Such a myriad of growth factors being released from the epithelium provides a strong stimulus for airway remodelling in certain asthma subtypes (Fig. 6). This together with the finding that repeated distortion of the epithelium in in vitro culture generates the secretion of remodelling growth factors [117] has led to the idea that repeated bronchoconstriction evokes such a response as a way of limiting airway closure produced by smooth muscle contraction (Fig. 5). Only when the response continues unabated will this impact on deleterious remodelling with the occurrence of an increasingly fixed component to the airflow obstruction and an accelerated loss of lung function over time. Additional contributing factors that have also been incriminated in remodelling include epithelial–mesenchymal transition in the presence of TGFβ family of growth factors [118] and the recruitment of ‘fibrocytes’ (mesenchymal stem cells) from the bone marrow via the circulation [119,120].

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Figure 5.  Concept of reactivation of the epithelial mesenchymal trophic unit in the pathogenesis of chronic asthma. Separate gene/environmental interactions come together during lung development to render the lung susceptible to asthma involving epithelial and mesenchymal interactions. An abnormally responsive epithelium with delayed repair leads to a chronic wound scenario with reciprocal signalling between the epithelium and underlying mesenchyme leading both to a microenvironment conducive to maintaining inflammation and to airway wall remodelling.

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Concluding comments

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References

Could the epithelium be the site of the origins of asthma? Epithelial patterning in early life involving such transcription factors as SOX2 and may well be the reason why asthma is largely restricted to the conducting airways and does not lead to an alveolitis [121]. Placing the epithelium and underlying structural cells rather than the T lymphocyte at the centre of asthma pathogenesis helps to identify novel therapeutic targets that are more to do with protecting the airways from environmental insults rather than suppressing aspects of inflammation. This new paradigm will present challenges, but by introducing it there is a chance that truly innovative upstream targets against which to develop therapeutics closer to the origins of the disease will occur. Finally, a recognition that asthma can no longer be considered as a single homogeneous disease entity with phenotypes that express aspects of asthma differently [122] creates an opportunity for novel diagnostic biomarkers linked to therapeutic responses can also be developed beyond the blockbuster approach to drug therapy as is now proving so successful in cancer treatment. As recently pointed out by Fahy [123], studies that have tackled issues of disease heterogeneity have been small, have used databases collected for other purposes and have limited ability to assign molecular phenotypes to clinical subtypes of disease. Now is the time to scale up clinical research in asthma to address such issues at a time when the number of adults with a lifetime asthma diagnosis continues to rise worldwide.

References

  1. Top of page
  2. Abstract
  3. Asthma: an historical perspective
  4. Description of asthma by William Osler
  5. Asthma mechanisms: early concepts
  6. Redefining immunological pathways in asthma
  7. Therapeutics emerging from mechanistic asthma research
  8. Time to change asthma paradigms: a forward look
  9. Asthma as a chronic wound of the conducting airways
  10. The significance of airway wall thickening
  11. Concluding comments
  12. Address
  13. References