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Keywords:

  • airway mucosa;
  • pharmacology;
  • thermoplasty;
  • TNF-alpha;
  • treatment

Abstract

  1. Top of page
  2. Abstract
  3. Pharmacological interventions
  4. Other immunosuppressive treatments
  5. Non-pharmacological interventions
  6. Perspectives on asthmatic airway sampling
  7. Summary
  8. References

Background:  Asthma is recognised as a condition with variable airway obstruction with pathophysiological features that include activation of a wide range of inflammatory and structural cells. Additionally, structural changes in the airways have been demonstrated. This includes increased thickening of components in the basement membrane region, increased smooth muscle mass, increased vascularisation and many other events that is often referred to as remodelling of the airways. These processes and the underlying mechanisms have attracted considerable attention.

Methods and Results:  This review describes the different interventive approaches that have been tried in order to improve asthma control and affect the underlying pathophysiological pathways. These include elimination of harmful environmental and occupational exposures, a wide range of pharmacological agents as well as bronchial thermoplasty. The existing evidence for effects on airway inflammation and airway remodelling is discussed in relationship to mechanistic aspects and short- and long-term outcome.

Conclusion:  It is expected that modulation of the asthmatic airway remodelling will become an even more important endpoint in the near future.

Please cite this paper as: Sandström T. Effects of pharmacological and non-pharmacological interventions. Clin Respir J 2010; 4 (Suppl. 1): 41–48.

The dynamic structural changes in asthma, that often are referred to as ‘remodelling’, have gained an increasing interest over the last years. Asthma is now considered as being not only an airway condition that involves mobile inflammatory cells that produce cytokines and other inflammatory modulating components, but also a multitude of activated resident and structural cells, together with extensive structural changes that are most evident in terms of thickening of the reticular basement membrane (RBM) region and epithelial fragility (Fig. 1). The thickening of the RBM, with increased deposition of matrix components, has been shown to correlate with the degree of bronchial hyperresponsiveness in asthmatic subjects, indicating that this structural change could be linked with important patho-physiological aspects of asthma (1). Hypertrophy of smooth muscle, nerves, vasculature, goblet cells and submucosal glands are other examples of structural alterations verified in asthma.

image

Figure 1. Bronchial mucosa in asthmatic subject with widespread structural changes associated with airway remodelling.

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A key issue considering interventions which may influence airway remodelling is whether these processes are beneficial or adverse for the patient, or possibly both. Irreversible airflow limitation in subjects with a previously clear history of asthma and absence of smoking is commonly considered as fixed airway obstruction because of remodelling changes of the airways. Increased stiffness and reduced compliance of the airway wall has been associated with enhanced matrix deposition that may be protective against excessive bronchoconstriction. On the other hand, an irreversible airway narrowing may just as well be an adverse reaction for the patient, who loses respiratory capacity. In very severe asthma, disruption of alveolar walls attaching to bronchi may occur and thereby adding to airway narrowing. The reduced luminal area because of submucosal thickening may increase the risk of airway closure, especially in combination with increased amounts of thick mucous and plugs. Taken together, there are indications of both pros and cons for airway remodelling. Repeated and severe bronchoconstrictive reactions may be limited by an increased stiffness of the airways that are less prone to reduce in diameter. On the other hand, remodelling changes that increase the stiffness and prevent rapid airway narrowing may in itself be associated with an increased thickness of the airway wall that reduces the airway lumen in a more or less fixed state (2–4). Consequently, it is important to consider the pros and cons of airway remodelling in order to correctly evaluate whether a certain intervention may be beneficial for the individual in short- and long-term perspectives.

Pharmacological interventions

  1. Top of page
  2. Abstract
  3. Pharmacological interventions
  4. Other immunosuppressive treatments
  5. Non-pharmacological interventions
  6. Perspectives on asthmatic airway sampling
  7. Summary
  8. References

Corticosteroids

Inhaled corticosteroids (ICS) have fundamentally changed the development and course of asthma over the last decades. This is the only drug class that is proven to decrease asthma mortality. An improvement in lung function with an emphasis on the benefit of early inhaled steroid introduction has been established as well as improvement in quality of life, exacerbations and hospitalisations (5–7). Different aspects of asthma have shown different time courses for improvement, with bronchial hyperresponsiveness being particularly slow and may still continue to improve 1 year after introduction of ICS medication. The relationship between the anti-inflammatory and remodelling modulating effects of corticosteroids in asthma in relationship with clinical and functional aspects is of considerable interest. With its wide anti-inflammatory potential, it could be expected that ICS would be able to ‘cure’ asthma. In clinical practice, most patients experience a fundamental improvement of asthmatic symptoms, and the prognosis of asthma also improves. Still, it appears that basic underlying mechanisms in asthma persist, and may make asthmatic symptoms reappear earlier or later in life and that corticosteroids cannot be seen as the ultimate ‘curing’ agent. The asthmatic airway remodelling processes may to some extent be improved by ICS. The effects are varying between investigations but include improvement of epithelial damage, reduction in inflammatory cells in particular eosinophils and T-cells. The RBM thickening may be at least partly reversible with reduced tenascin deposition (1, 8–10).

Chakir et al. investigated the effects of 2-week oral corticosteroid treatment in moderately to severe asthma (11). The subjects were investigated with bronchoscopies with bronchial mucosal biopsies sampling. The authors were able to demonstrate reduced expressions of interleukin (IL)-11 and IL-17 positive cells; cells that may represent modulation of T-cell function by steroids. More importantly, the profibrotic factor TGF-β expression was unaffected by the oral corticosteroids, as were the collagen I and III expressions. These remodelling-associated factors were also higher in patients with more severe asthma than a reference asthmatic population with mild disease. The short duration of the treatment makes it impossible to judge whether somewhat longer systemic corticosteroid treatment could give more extensive effects in reversing remodelling processes. TGF-β is an interesting factor that has increasingly come into focus in the patho-physiological views of remodelling in asthma. The low sensitivity to glucocorticoids of this factor has led to research into alternative and more specific pathways to modulate its production as well as ability to activate other cells.

β2-agonists

The effects of β2-agonists on airway remodelling have been addressed in some animal models of asthma. It can be noted that investigations in rats have suggested potential adverse effects by salbutamol treatment. An increased bronchial hyperresponsiveness and goblet cell hyperplasia have been common events in allergen-sensitised rats (12, 13). Continuous treatment with salbutamol over 4 weeks was almost doubled bronchial responsiveness to metacholine, but also doubled the numbers of goblet cells. The goblet cell hyperplasia was not present in non-salbutamol treated animals and was completely abolished by prednisolone. Cell experiments have pointed towards G-protein receptor-coupled stimulation by s-albuterol on mitogenic factors stimulating smooth muscle hyperplasia (14). This may be counteracted by the levo-albuterol isomer. Cell culture experiments with human fibroblasts have shown salbutamol, formoterol and beclomethasone alone, and in combination, to give suppressive effects on fibroblast proliferation and fibrotic remodelling processes (15).

Several bronchoscopy studies have been performed in asthmatics investigating local airway effects of β2-agonists. To the major extent, these studies have been focused on and demonstrated suppressive effects on inflammatory cells like eosinophils and mast cells, rather than structural changes related to remodelling processes (16, 17). This appears partly to reflect the research questions of the time when they were performed. Effects of combination therapy with long-acting β2-agonist (LABA) and inhaled corticosteroid treatment on remodelling aspects of asthma have recently been reported (18). Thirteen patients with mild to moderate asthma were investigated with bronchoscopy and biopsy sampling before and after 6-month treatment with formoterol and budesonide. Baseline data were also compared with a 10-subject control group and the asthmatic subjects showed clear evidence of airway remodelling correlating positively with bronchial hyperresponsiveness and negatively with lung function. Following 6-month treatment, vascular endothelial growth factor (VEGF) and VEGF-receptor-1 (VEGFR1) expressions in the airways were significantly reduced and this correlated with indications of decreased remodelling changes in the airways. The authors reported significant reductions in submucosal gland hyperplasia, smooth muscle mass, RBM thickness and subepithelial fibrosis. In a subsequent in-vitro study, treatment with salmeterol alone and in combination with fluticasone was shown to give a similar inhibition of VEGF together with fibroblast growth factor-2 (FGF-2) in BEAS-2B cells after incubation with rhinovirus, a common trigger in asthma (19, 20).

Antileukotrienes

Cysteinyl-leukotrienes are potent bronchoconstrictive agents with pro-inflammatory properties shown to be of importance in asthma (22). Potential modulating effects by montelukast on allergic inflammation and airway remodelling have been investigated in some rat and mouse models. Interestingly, montelukast treatment has been shown to reduce smooth muscle hyperplasia as well as collagen deposition in the airways in allergen-sensitised rodents. These effects correspond with remodelling changes in asthma in humans, which are associated with reduced bronchial hyperresponsiveness (22, 23). Further development of this research line is consequently of interest. Leukotriene antagonist treatment has over the last years found its way into clinical practice of asthma. Bjermer and co-workers reported from a large-scale study that they found relatively similar effects of montelukast to those of LABA (24).

Comparative studies with inhaled corticosteroids at different doses have mainly been performed with montelukast vs fluticasone propionate (FP). In one study, 28 asthmatic subjects underwent bronchoscopy before and after 8-week treatment with 100 µg FP, with and without the addition of montelukast (25). No additive effects of leukotriene antagonism were seen, in bronchial biopsies or soluble components, to those produced by the inhaled steroid alone. This has been interpreted by some authors as anti-leukotrienes not having major additive effects to those broader anti-inflammatory effects of ICS in asthmatic subjects. Longer studies in larger groups of asthmatic subjects may be needed to determine the long-term effects, especially for the effects on remodelling.

Anticholinergics

Anticholinergic treatment in asthma has found its way into emergency room situations where ipratropium bromide may be inhaled, usually together with a β2-agonist. The primary indication for maintenance treatment with anticholinergics is, however, chronic obstructive pulmonary disease (COPD). The influence of anticholinergic treatment has nevertheless been explored in an animal model of asthma based on the hypothesis that growth factor-induced smooth muscle proliferation is enhanced by acetylcholine. Allergen challenge in guinea pigs resulted in hypertrophy of smooth muscle after 12 weeks, which was restricted to the peripheral non-cartilaginous airways. Tiotropium treatment was shown to inhibit the allergen-induced increases of airway smooth muscle mass, myosin expression and contractility(26). The study may therefore indicate that muscarinic M3-stimulation could increase the sensitivity of the bronchial smooth muscle for growth factors and inflammatory mediators, and that blockade could be beneficial. If so, this would be interesting to explore in human subjects with asthma or COPD, but to date no such data have been published.

Anti-IL-5

Anti-IL-5 is one of several interesting approaches to block suggested eosinophilic components in asthma. An immediate success has escaped after the early studies in asthmatics with IL-5 antagonism (27, 28). The rationale for this approach has been the perception that eosinophils and eosinophil-derived TGF-β may play a major role in chronic asthma and airway remodelling. Reductions in blood and induced sputum eosinophils have been shown in trials in asthmatic subjects, but the reductions have not been complete and clinical effects have been elusive. Bronchial biopsies were sampled in 24 allergic asthmatic subjects before and after 10 weeks of treatment with anti-IL-5 administration (29). Eosinophil numbers and eosinophil TGF-β mRNA reduced together with significant reduction in tenascin, lumican and procollagen-III expression in the RBM compared with placebo. Why this was not translated into clinically meaningful improvement in asthma remains to be elucidated. This fact draws further attention to the question on whether remodelling changes in the RBM region and elsewhere in the asthmatic airways are for good or bad, or even both.

Anti-IgE treatment

Omalizumab is the first antibody treatment against asthma that has hit the market worldwide. The label refers to allergic asthma with more severe cases in focus in Europe, with wider indications in the United States and certain other areas of the world. Overall, the clinical evidence supports the fact that this medication facilitates a reduction in the dose of oral and inhaled glucocorticoids in patients with allergic asthma. Biopsy sampling both from the nose and from bronchi has demonstrated significantly reduced mucosal inflammatory cell infiltration including eosinophils, T-cells and B-cells and IL-4 positive cells (30, 31). This was accompanied by suppression of the number cells positive for the high-affinity IgE receptor (FCεRI) as well as overall IgE positive cells. Data on structural changes related to remodelling of the asthmatic airways are yet to emerge and are important for a more complete understanding of this immune modulating treatment in asthma.

Anti-TNFα

TNFα is a common pleiotropic cytokine indicated to be of importance in a number of inflammatory conditions including rheumatoid arthritis, Crohn's disease, psoriasis and others. Successful treatments with anti-TNFα antibodies and soluble receptors have established themselves in these conditions. TNFα has been implicated in asthma in studies of genetic associations as well as animal models. Howarth and colleagues have demonstrated the TNFα expression in asthmatic airways to be mainly present in mast cells and that severe asthmatics had substantially higher expression than mild-moderate asthmatics as well as healthy controls (32). In an open treatment study, 17 severe asthmatic individuals were followed during 12 weeks of treatment with etanercept, a soluble TNFα receptor-IgG1 fusion protein. This study demonstrated improvement in asthma symptoms, lung function and bronchial hyperresponsiveness, as endorsed by more recent research (33). A placebo-controlled study with etanercept treatment over 10 weeks in severe refractory asthma gave additional support for effectiveness of the treatment by significantly improving asthma symptoms, lung function and bronchial hyperresponsiveness (34). Studies on efficacy on asthma remodelling are to be expected in the near future.

Other immunosuppressive treatments

  1. Top of page
  2. Abstract
  3. Pharmacological interventions
  4. Other immunosuppressive treatments
  5. Non-pharmacological interventions
  6. Perspectives on asthmatic airway sampling
  7. Summary
  8. References

There is presently limited data on the efficacy of other immunosuppressive treatments such as azathioprin, methotrexate and ciclosporin in asthma. There is no published evidence for remodelling effects in asthmatic airways.

Non-pharmacological interventions

  1. Top of page
  2. Abstract
  3. Pharmacological interventions
  4. Other immunosuppressive treatments
  5. Non-pharmacological interventions
  6. Perspectives on asthmatic airway sampling
  7. Summary
  8. References

Interventional studies in asthma can be done in many ways, with the clear majority being pharmacological studies evaluating the efficacy of different strategies. However, another important study model is to reduce noxious agents and determine the efficacy of this intervention in asthmatic subjects.

Elimination studies

Toluene di-isocyanate (TDI) is an industrial agent that has been recognised to elicit and worsen asthmatic symptoms. Cessation of exposure is paramount to avoid increased severity of symptoms and chronic severe condition. Saetta and co-workers have investigated TDI effects in a series of investigations using both animal models and studies in human subjects. Of particular interest was a bronchoscopy study conducted on occupational asthma related to TDI exposure (35). Patients were examined at the time of diagnosis as well as 6 months after cessation of exposure (35). The analyses of bronchoscopy samples from these patients were compared with corresponding analyses from control subjects. An increased thickening of the RBM was found together with increase numbers and degranulation of mononuclear cells and eosinophils in the TDI asthma subjects. The termination of exposures was found to be successful in reversing the thickening of the RBM which returned to normal. The asthmatic symptoms also improved in the absence of TDI exposure. Six months after cessation of exposure, an increase in airway hyperresponsiveness to metacholine still persisted and so did the infiltration of inflammatory cells and signs of degranulation of these cells in the airway wall. The study indicates that at least at a relatively early stage, structural changes may reverse after termination of a noxious exposure like TDI to the airways, but that the outcome of bronchial hyperresponsiveness and cell activation may follow other time lines.

Other types of occupational asthma have also been investigated. Sumi et al. investigated 10 subjects with occupational asthma with a mean duration of 14 years (range 0.5–21 years) since ceasing the specific occupational exposures (36). All were symptom-free with normal lung function and metacholine test. Bronchoscopies with bronchoalveolar lavage and bronchial biopsies where performed. A persisting increase in sub-epithelial fibrosis, determined by increased collagen amounts and visualised by van Gieson staining was present in the occupational asthma group compared with controls. This thickening significantly reduced the distance between the epithelium and airway smooth muscle. The patients with occupational asthma displayed increased numbers of TGFβ1- and ECP-positive cells vs controls, but no increase in inflammatory cells or changes in structural cells. The study suggests that some structural changes may persist long after cessation of occupational exposures, even in the absence of asthmatic symptoms and functional deficits.

House dust mite sensitisation is a major problem for allergic asthmatics worldwide. Encasement of bedding has therefore been investigated as a means to reduce exposure to Dermatophagoides pteronyssinus (Derp2) allergen. This has been addressed by several investigators without major effects on quality of life, lung function and symptoms (37, 38). The lack of successful interventive studies makes it difficult to determine the role of house dust mite for remodelling of asthmatic airways both on causative and temporal levels.

Bronchial thermoplasty

Bronchial thermoplasty refers to an electro-mechanical treatment using radiofrequency ablation whereby the airway wall is heated by a wire instrument inserted through the bronchoscopy channel (Fig. 2). This particular treatment has been suggested to give a permanent effect on the smooth muscle in the airways walls, but little effect on the surrounding tissue. Morphological investigations in dogs indicate loss of smooth muscle in the treated airway segments, but recovery of the more superficial structures such as the epithelium, as demonstrated in investigations, as assessed by Hogg and co-workers(39, 40). The bronchial lumen appears dilated after treatment, and remain wider at resting state as well as after metacholine provocation, as visualised by computerised tomography (CT) scans (41).

image

Figure 2. Bronchial thermoplasty with a wire basket catheter inserted through the bronchoscopy channel. With permission from Asthmtx Inc., Sunnyvale, CA.

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A major study has been published studying thermoplasty effects in 112 subjects with moderate to severe asthma with FEV1 60%–85% of predicted during treatment with ICS and LABA, and all showing significant symptom flare up during a 2-week LABA withdrawal. All subjects showed bronchial hyperresponsiveness with PC20 < 8 mg/mL during metacholine tests and were stable for at least 6 weeks prior to randomisation to bronchial thermoplasty or placebo. Symptoms, rescue medication and exacerbations were all significantly reduced after thermoplasty. Metacholine responsiveness, though, was not significantly affected in this material (42).

As estimated by the preceding research performed in animals, the asthmatic subjects treated with bronchial thermoplasty would have experienced an irreversible destruction of airway smooth muscle and reversible damage to other parts of the airway mucosa, in the parts of the major bronchi which were treated. More peripheral parts of the airways would be expected to be unaffected. The bronchial thermoplasty approach represents, by far, the most extensive remodelling of asthmatic airways by any treatment. Placebo-controlled investigations with more detailed description of the resulting structural airway changes in asthmatic subjects by bronchial biopsies and other techniques may assist this novel treatment option to find its scientific and clinical position.

Perspectives on asthmatic airway sampling

  1. Top of page
  2. Abstract
  3. Pharmacological interventions
  4. Other immunosuppressive treatments
  5. Non-pharmacological interventions
  6. Perspectives on asthmatic airway sampling
  7. Summary
  8. References

There are certain advantages and disadvantages with the current available techniques to evaluate the potential remodelling processes in the lungs of asthmatics. They give valuable opportunities but are also somewhat limited in their capacity to give an overall detailed view of the whole bronchial tree and lung tissue that may be involved in the condition we refer to as asthma.

Bronchial mucosal biopsies sampled during flexible bronchoscopy are usually relatively superficial and may only to a limited extent reach down into the smooth muscle layer. There are deeper areas from which tissue may not regularly be reached. It is clear that it is not possible to evaluate the whole depth of the airway wall by relatively superficial biopsies. Apart from the depth issue, there are also regional aspects on sampling from the bronchial tree. Biopsies are normally taken within the visual range, i.e. first to third generation cristae. Transbronchial biopsies that add information on bronchioli and alveoli have only been used in a few studies by certain investigators (43). This has added some new information, but it is obvious that there are a number of generations between the proximal biopsies and the transbronchial, which have not been harvested to any large extent. Occasionally, brushings of smaller airways have been examined. Bronchial washes with small volumes like 20 mL may sample cells and superficial components from bronchi and possibly from bronchioli, which can give some information. Bronchoalveolar lavage with larger volumes as 100–300 mL may give recovery mainly from the alveolar surfaces where asthma, however, does not seem to be extensively active. Induced sputum has benefits by sampling secretions provoked by hypotonic saline. Airway wall thickness and distribution between different structure components is clearly limited and CT scans and magnet resonance may be tools for the future to give a broader understanding of changes in the airway system. Some preliminary studies have provided encouraging information (44, 45). It is also clear that any method which gives information over larger areas of the lungs may better control for regional variability in structural changes.

Summary

  1. Top of page
  2. Abstract
  3. Pharmacological interventions
  4. Other immunosuppressive treatments
  5. Non-pharmacological interventions
  6. Perspectives on asthmatic airway sampling
  7. Summary
  8. References

Asthma is associated with remodelling changes in the airways including increased thickening of the basement membrane region as well as other structural changes. The role of these changes has attracted considerable interest. Certain, positive effects on airway remodelling have been demonstrated following cessation of harmful occupational exposures and also to some degree for some of today's pharmacological agents. The most profound changes in airway structure have been seen following bronchial thermoplasty which reduces bronchial smooth muscle mass, associated with positive effects on asthma control at least during the limited follow-up period.

References

  1. Top of page
  2. Abstract
  3. Pharmacological interventions
  4. Other immunosuppressive treatments
  5. Non-pharmacological interventions
  6. Perspectives on asthmatic airway sampling
  7. Summary
  8. References
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