Review
Pharmacology of airway inflammation in asthma and COPD

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Abstract

The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long term treatment. Although inhaled glucocorticoids are highly effective in controlling airway inflammation in asthma, they are ineffective in the small group of patients with glucocorticoid-dependent and -resistant asthma. With very few exceptions, COPD is caused by tobacco smoking, and smoking cessation is the only truly effective treatment of COPD available. Current pharmacological treatment of COPD is unsatisfactory, as it does not significantly influence the severity of the disease or its natural course. Glucocorticoids are scarcely effective in COPD patients without concomitant asthma. Bronchodilators improves symptoms and quality of life, in COPD patients, but, with the exception of tiotropium, they do not significantly influence the natural course of the disease. Theophylline is the only drug which has been demonstrated to have a significant effect on airway inflammation in patients with COPD. Here we review the pharmacology of currently used antiinflammatory therapies for asthma and COPD and their proposed mechanisms of action. Recent understanding of disease mechanisms in severe steroid-dependent and -resistant asthma and in COPD, has lead to the development of novel compounds, which are in various stages of clinical development. We review the current status of some of these new potential drugs.

Introduction

In this article we will review the pharmacology of the principal drugs currently used to treat airway inflammation in bronchial asthma and chronic obstructive pulmonary disease (COPD). Most of the studies reviewed here have been performed on bronchial asthma, whereas very few controlled studies have been published on tobacco smoking-related COPD. Inflammation is a central feature of asthma and COPD. The specific characteristics of the inflammatory response in each disease and the site of inflammation differ but both involve the recruitment and activation of inflammatory cells and changes in the structural cells of the lung. Asthma and COPD are characterized by an increased expression of components of the inflammatory cascade including cytokines, chemokines, growth factors, enzymes, receptors and adhesion molecules. The increased expression of these proteins seen in asthma and COPD is the result of enhanced gene transcription since many of the genes are not expressed in normal cells but are induced in a cell-specific manner during the inflammatory process. Although there has been an explosion of research on asthma and a revolution in asthma therapy, COPD has been surprisingly neglected, with little research into cellular mechanisms and few advances in therapy [1]. However, it is increasingly apparent that this is an important disease whose incidence is rising worldwide and that there is a need to develop new treatments to prevent the progression of the disease, which results in a large consumption of health care resources [1]. This recognition has led to a revival of research on mechanisms of COPD, involving new molecular approaches and a search for treatments that will halt progression of the disease [1]. We briefly summarise at the end some new classes of drugs under development for asthma and COPD.

Section snippets

Asthma is a chronic inflammatory disease of the airways

Asthma is a chronic inflammatory disorder of the airways in which many cells and elements play a role. The chronic inflammation is associated with increased airway hyperresponsiveness leading to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment [2]. The chronic airway

COPD is a chronic inflammatory disease of the lower airways

Despite all asthma guidelines defining asthma as a chronic inflammatory disease of the lower airways, current COPD guidelines do not include the presence of lower airways inflammation in their definitions [4], [5], [6], [7]. COPD has been increasingly recognized as a chronic inflammatory disease of the lower airways, which is enhanced during exacerbations [1]. The pathological hallmarks of COPD are destruction of the lung parenchyma (pulmonary emphysema), inflammation of the peripheral airways

Clinical effects

Pharmacological control of asthma may be obtained in most asthmatics with anti-inflammatory agents (controllers), i.e. inhaled glucocorticoids and theophylline (Table 1). The most potent controllers are the inhaled glucocorticoids [11], [12]. In most asthmatic patients adequate doses of inhaled glucocorticoids, particularly if combined with long-acting bronchodilators, allow systemic glucocorticoids to be reduced or withdrawn completely [13], [14].

Glucocorticoids consistently lessen airway

New drugs which can potentially interfere with pro-inflammatory pathways in the lungs of asthma and/or COPD patients

Many new drugs are now in development for the treatment of asthma (Table 5). There has been an intensive search for anti-inflammatory treatments for bronchial asthma that are as effective as glucocorticoids but with fewer side effects [309]. Whereas one approach is to seek glucocorticoids with a greater therapeutic effect, other approaches involve developing different classes of anti-inflammatory drugs [309]. Selective inhibition of Th2 cells may be more effective and better tolerated and there

Asthma

Many clinical and pathological studies suggest that the small airways (<2 mm in diameter) are involved in the pathogenesis of the chronic airflow obstruction that develop in some patients with persistent asthma [316]. Recently, the introduction of hydrofluoroalkanes (HFAs) as propellants in pressurised metered-dose inhalers (pMDIs) has allowed for the erogation of smaller particles of the drug, increased (4- to 5-fold) deposition in the lungs and increased delivery of the drug to the small

Selective inhibitors of phosphodiesterase 4

A class of promising novel anti-inflammatory treatment for asthma and COPD are the selective inhibitors of phosphodiesterase 4 (PDE4). PDE4 is expressed in macrophages, neutrophils, CD8+ T cells and airway smooth muscle cells. These compounds inhibit the hydrolysis of intracellular cAMP, which may result in bronchodilation and suppression of inflammation. There are many compounds in this new class of drugs in clinical development; however, most of the clinical studies have been performed until

New histamine H1 receptor antagonists

Second-generation histamine H1 receptor antagonists (antihistamines) have been developed to reduce or eliminate the sedation and anticholinergic adverse effects that occur with older H1 receptor antagonists [329]. They include acrivastine, astemizole, azelastine, cetirizine, desloratadine, ebastine, fexofenadine, ketotifen, levocetirizine, loratadine, mizolastine, norastemizole and terfenadine [329]. In addition to their primary mechanism of antagonising histamine at the H1 receptor, and their

Chemokines and chemokine receptors antagonists

The chronic airway inflammation associated with asthma and COPD result in the co-ordinated recruitment of different inflammatory cells in the lungs. This cellular influx is finely regulated through the temporal and spatially regulated expression of chemokines, which potentiate the migration of cells along gradients of chemotactic ligands [333]. Chemokines act as ligands for the chemokine receptors; a distinct class of G-protein-coupled receptor. About 50 distinct chemokine ligands and 20

Transcription factor inhibitors

Asthma and COPD are characterized by an increased expression of components of the inflammatory cascade. These inflammatory proteins include cytokines, chemokines, growth factors, enzymes, receptors and adhesion molecules [350]. The increased expression of these proteins seen in asthma and COPD is the result of enhanced gene transcription since many of the genes are not expressed in normal cells but are induced in a cell-specific manner during the inflammatory process. Changes in gene

Antioxidants, mucolytic and mucokinetic drugs

Oxidative stress is increased in COPD, particularly during exacerbations and reactive oxygen species may contribute to the pathogenesis of lung damage [356]. The available antioxidants (some also with mucolytic and mucokinetic properties such as acetylcysteine and ambroxol) have been employed in the treatment of COPD with conflicting results [356]. However, it is likely that more effective antioxidants compounds will be developed in future.

TNFα

Tumor necrosis factor-alpha (TNF-α), a multifunctional cytokine, is released in the airways from mast cells, alveolar macrophages and CD8 T lyphocytes [357] and elevated levels of TNF-α have been demonstrated in the bronchial biopsies and sputum from asthmatic and COPD patients [358], [359]. TNF-α levels in BAL increase after allergen challenge in atopic asthmatics [360]. In addition, TNF-α is an important chemotactic protein for neutrophils. In fact the inhalation of TNFα induces sputum

IL-10

IL-10 is produced by several cell types, including monocytes, macrophages, T lymphocytes, dendritic cells and mast cells [361]. IL-10 is a unique cytokine with a wide spectrum of anti-inflammatory effects. It inhibits the secretion of TNF-a and IL-8 from macrophages and tips the balance in favour of antiproteases by increasing the expression of endogenous tissue inhibitors of MMPs (TIMPS) [361], [372]. Some of the actions of IL-10 can be explained by an inhibitory effect on NF-κB, but this does

Induction of regulatory-lymphocytes in the lungs

The ‘hygiene hypothesis’, suggests that the increase in allergic diseases is caused by a cleaner environment and fewer childhood infections. Indeed, certain mycobacterial strains can cause a shift from Th2 to Th1 immune responses, which may subsequently prevent the development of allergy in mice [388]. This attractive theory is unlikely to explain the whole story, as the prevalence of autoimmune diseases characterized by Th1 responses has also increased in parallel to allergies [388]. Treatment

Immunostimulatory sequence oligodeoxynucleotide (ISS-ODN)-based immunotherapy

Among different methods designed to redirect allergen-specific Th2 responses, conjugation of the antigen to appropriate immunostimulatory oligodeoxynucleotides (ISS-ODNs) seems to be highly promising [393]. In animal models, DNA containing unmethylated cytosine-phosphate-guanine (CpG) motifs provide Th1 adjuvant activity for the immune response [394]. Through their recognition by the toll-like receptor (TLR) 9, expressed predominantly on the surface of the dendritic cells, macrophages, B

Tachykinin antagonists

Tachykinin (substance P, neurokinins) levels are increased in induced sputum from COPD patients [397]. Neurogenic inflammation may play a role in COPD, particularly in the pathogenesis of mucus hypersecretion [398] and thus tachykinins antagonists and sensory neuropeptide release inhibitors may represent potential new pharmacological agents. To date published clinical data on the effects of tachykinin receptor antagonists in COPD are scarce and specific data on their effects on mucus production

Conclusions

The current asthma therapies are not cures and symptoms return soon after treatment is stopped even after long-term therapy [22]. Although glucocorticoids are highly effective in controlling the inflammatory process in asthma, they appear to have little effect on the remodelling processes that appear to play a role in the pathophysiology of asthma at currently prescribed doses [76]. The development of novel drugs or treatment regimes may allow resolution of these changes [76]. In addition,

Acknowledgements

Supported by Associazione per la Ricerca e la Cura dell'Asma (ARCA, Padua, Italy), The British Lung Foundation, The Clinical Research Committee (Brompton Hospital) and GlaxoSmithKline (UK).

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