Adenosine receptors as promising therapeutic targets for drug development in chronic airway inflammation

A growing body of evidence has emerged in support of a pro-inflammatory role for adenosine in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and COPD. The demonstration that adenosine enhances mast cell allergen-dependent activation, the notion that elevated levels of adenosine are present in chronically inflamed airways, and the results from exposure studies of nebulised adenosine showing dose-dependent bronchoconstriction in subjects with asthma and COPD, emphasise the importance of adenosine in the initiation, persistence and progression in these common inflammatory disorders of the airways. Adenosine exerts its manifold biological activities by interacting with at least four adenosine receptor subtypes. Selective activation or blockade of these sites is being exploited by the pharmaceutical industry in an attempt to generate novel therapies for asthma and COPD. This review article intends to address the potential role of adenosine in asthma and to put forward the idea that drugs that have been developed to selectively activate or downregulate adenosine receptor subtypes may constitute a considerable advance in the management of chronic airway inflammation.     

Oxidants in asthma and in chronic obstructive pulmonary disease (COPD)

Experimental and clinical evidences suggest that oxidants play a role in the pathogenesis of respiratory disorders characterised by chronic airway inflammation such as asthma and chronic obstructive pulmonary disease (COPD). The respiratory system is chronically exposed to environmental pollutants, including oxidants. Exogenous sources of oxidants are particularly relevant to the pathogenesis of COPD, being cigarette smoke an extremely rich source of oxidants. In addition, the inflammatory cells recruited to the airways of patients with asthma and COPD, have an exceptional capacity to produce oxidants. Many decades of research have produced a significant amount of data indicating pro-oxidative molecular mechanisms putatively relevant in the pathogenesis of the oxidative stress which characterises these diseases, both locally and systemically. As a consequence, a drug therapy able to restore the redox imbalance in asthma and COPD would probably exert clinical and functional benefits. Indeed, currently available therapies for asthma and COPD can exert an inhibitory effect on oxidant production in the airways. However, it is unknown whether the efficacy of the treatment is somehow linked to the pharmacological modulation of the oxidant/antioxidant balance. So far, it appears that the potential role of antioxidant compounds in the treatment of asthma and COPD has not been fully explored.     

Emerging oligonucleotide therapies for asthma and chronic obstructive pulmonary disease

Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) are disorders of the airways largely related to the presence of persistent inflammation. The approval of inhaled corticosteroids in the early 1970s pioneered a new age of therapy in treating chronic inflammatory airway diseases. This was the first time that an anti-inflammatory product was available to reduce the characteristic lung inflammation in airways and the associated obstruction, inflammation and hyper-responsiveness. Fast forward 40 years: corticosteroids are still an important therapeutic intervention; however, they exhibit limited use in moderate to severe asthma and COPD. Oligonucleotide therapies are an emerging class which include the antisense, the RNAi (siRNA and miRNA), the immunomodulatory, the aptamer and the decoy approaches. As these approaches are rather recent in the respiratory field, most are still early in development. Nevertheless, with limitations of current small molecule therapies and the hurdles faced with biologics, the use of oligonucleotides is relevant and the door is open to the development of this category of therapeutics. This review focuses on the major classes of oligonucleotides that are currently in late stage preclinical or clinical development for the treatment of asthma and COPD, and discusses the implications for their use as therapies for respiratory diseases.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. β-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. Beta-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

Role of adenosine receptors in the treatment of asthma and chronic obstructive pulmonary disease: recent developments

Adenosine is a naturally occurring purine nucleoside with a ubiquitous presence in human tissue, where it plays a key role in many biological processes such as energy generation and protein metabolism. It has been shown that adenosine induces bronchoconstriction in asthmatic and chronic obstructive pulmonary disease (COPD) patients, but not in normal airways. Four different G-protein-coupled adenosine receptors have been described, namely adenosine A(1), A(2A), A(2B) and A(3) receptors. The main mechanism of adenosine-induced bronchoconstriction appears to involve the release of inflammatory mediators from mast cells via activation of the A(2B) receptor. However, adenosine can also act on A(1), A(2A) and A(3) receptors. In recent years there has been an increasing interest in the role of adenosine receptors in asthma and COPD, since it is now clear that they play an important role in the pathophysiology of asthma and COPD. Adenosine receptors are involved in the production and release of a variety of mediators from inflammatory and structural cells. A therapeutic potential for adenosine receptor modulation has even been anticipated. This review focuses on the role of adenosine and adenosine receptors in the treatment of asthma and COPD.     

Small molecule inhibitors of cell signaling: novel future therapeutics for asthma and chronic obstructive pulmonary diseases

The respiratory diseases asthma and chronic obstructive pulmonary disease (COPD) exhibit common, key pathological features, including the development of airflow limitations such as thickening of the airway wall, and the presence of an inflammatory process. However, that is where their similarities end. A large number of medications for asthma are available to decrease inflammation and prevent or reverse airway constriction, while very few therapeutics, if any, exist for the effective management of COPD. Nonetheless, despite the availability of medications for asthma, the epidemic is continuing to increase and existing therapies offer little or no relief for chronic asthmatics. It is obvious that a high, unmet medical need remains for both asthma and COPD, and innovative therapeutic agents are urgently required. New therapies need to be developed to target not only the inflammatory component of asthma and COPD, but also the remodeling aspects of these diseases. This review summarizes the emerging treatments for chronic asthma and COPD, from early discovery to late clinical stages, and discusses the therapeutic rationale behind these treatments. We believe that there is still much to be learned about the mechanisms involved in the development and treatment of these debilitating respiratory diseases, however, much promise lies in the future of these new therapeutics.     

Inflammasome signaling in pathogenesis of lung diseases

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are two important lung and airways diseases which affect the lives of ～500 million people worldwide. Asthma is a heterogeneous disease that is broadly defined as a clinical syndrome characterized by altered lung function, mucus hypersecretion, peribronchial inflammation and hyperresponsiveness In contrast, the effect of inhalation of toxic particles and gases on the innate and adaptive inflammatory immune systems underlie the pathogenesis of COPD. In the last decade, knowledge concerning the pathophysiologic mechanisms underlying asthma and COPD has risen tremendously and current dogma suggests that the pathogenesis of both diseases is driven by the chronic inflammation present in the airways of these patients. Thus, understanding the mechanisms for the persistence of inflammation may lead to new therapeutic approaches. In this review, we provide an overview of the main signal transduction pathways implicated in asthma and COPD pathophysiology focusing on inflammasome signaling in various cells types which result in altered inflammatory mediator expression.     

RAGE: a new frontier in chronic airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand–RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.     

Dual role of Toll-like receptors in asthma and chronic obstructive pulmonary disease

During the last decade, significant research has been focused on Toll-like receptors (TLRs) in the pathogenesis of airway diseases. TLRs are pattern recognition receptors that play pivotal roles in the detection of and response to pathogens. Because of the involvement of TLRs in innate and adaptive immunity, these receptors are currently being exploited as possible targets for drug development. Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory airway diseases in which innate and adaptive immunity play an important role. To date, asthma is the most common chronic disease in children aged 5 years and older. COPD is prevalent amongst the elderly and is currently the fifth-leading cause of death worldwide with still-growing prevalence. Both of these inflammatory diseases result in shortness of breath, which is treated, often ineffectively, with bronchodilators and glucocorticosteroids. Symptomatic treatment approaches are similar for both diseases; however, the underlying immunological mechanisms differ greatly. There is a clear need for improved treatment specific for asthma and for COPD. This review provides an update on the role of TLRs in asthma and in COPD and discusses the merits and difficulties of targeting these proteins as novel treatment strategies for airway diseases. TLR agonist, TLR adjuvant, and TLR antagonist therapies could all be argued to be effective in airway disease management. Because of a possible dual role of TLRs in airway diseases with shared symptoms and risk factors but different immunological mechanisms, caution should be taken while designing pulmonary TLR-based therapies.     

Research applications and implications of adenosine in diseased airways

Adenosine, when given by inhalation, initiates the narrowing of airways in subjects with asthma or chronic obstructive pulmonary disease (COPD). The underlying mechanism of this narrowing appears to involve the stimulation of specific mast cell surface adenosine receptors with the subsequent release of mediators and contraction of airway smooth muscle. Although methacholine and histamine have become gold standards as bronchial provocants used to quantify bronchial hyperresponsiveness, the airways response to the indirect stimulus adenosine more closely reflects bronchial inflammation. This distinctive feature of adenosine could be exploited to enable superior diagnostic discrimination between asthma and COPD, allow better monitoring of disease activity and progression, and improve the individual adjustment of long-term asthma management with topical glucocorticosteroids. In this article, we review recent developments in this area of rapidly evolving clinical research, focusing on the putative role of adenosine as a mediator of airway inflammation and as a useful bronchoprovocant in several clinical and research applications.     

Oxidative stress and lung inflammation in airways disease.

Oxidative stress results from an oxidant/antioxidant imbalance in favour of oxidants. A large number of studies have demonstrated that increased oxidative burden occurs in airways diseases, shown by increased marks of oxidative stress in the airspaces and systemically in these patients. There is now substantial evidence that oxidative stress plays an important role in the injurious and inflammatory responses in airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). In addition to these proinflammatory mechanisms resulting from oxidative stress, protective mechanisms such as the upregulation of protective antioxidant genes also occur. At present, effective antioxidant therapy that has good bioavailability and potency is not available. Such drugs are being developed and should in the future allow the hypothesis that oxidative stress is a fundamental factor in the inflammation, which occurs in these airways diseases to be tested.     

COPD: is there light at the end of the tunnel?

No currently available treatments reduce the progression or suppress the inflammation of chronic obstructive pulmonary disease (COPD). However, with a better understanding of the inflammatory and destructive process, several targets have been identified and new treatments are in clinical development. Several specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, including adhesion molecule and chemokine-directed therapy, as well as therapies to inhibit tumour necrosis factor-alpha. Several broad-spectrum anti-inflammatory drugs are also in development, and include inhibitors of phosphodiesterase-4, p38 mitogen-activated protein kinase and nuclear factor-kappaB. There is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.     

Novel therapies for the treatment of inflammatory airway disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the current century. The beta-agonists and corticosteroids form the basis of the treatments available to alleviate the symptoms of asthma, whereas the treatments available for COPD have been shown to have a limited effect on slowing the progression of the disease. Asthma and COPD are both in need of novel, safe treatments to tackle the underlying inflammation that characterises their pathology. The inflammatory processes inherent in asthma and COPD provide the opportunity for innovative drug research. This review will outline the new approaches and targets being investigated, which may provide opportunities for novel therapeutic interventions in these debilitating diseases.     

Combining inhaled glucocorticoids and long acting beta(2)-adrenoceptor agonists in asthma and COPD

Inhaled long-acting beta(2)-adrenoceptor agonists and glucocorticoids form the mainstay of maintenance treatment of asthma and chronic obstructive pulmonary disease (COPD), usually given as a combination inhaler. Most patients will have good asthma control if they comply with this therapy, although it is generally less effective in COPD. The traditional dogma has been that these agents act on distinct components of disease pathophysiology with beta(2) agonists acting on the bronchospastic component and glucocorticoids acting on the inflammatory component. Considerable evidence has emerged recently, however, to suggest that these two classes of agents interact at a molecular level. Understanding the mechanisms of these interactions may enable the development of new therapies for asthma and COPD.     

Novel therapies for the treatment of inflammatory airway disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the current century. The β-agonists and corticosteroids form the basis of the treatments available to alleviate the symptoms of asthma, whereas the treatments available for COPD have been shown to have a limited effect on slowing the progression of the disease. Asthma and COPD are both in need of novel, safe treatments to tackle the underlying inflammation that characterises their pathology. The inflammatory processes inherent in asthma and COPD provide the opportunity for innovative drug research. This review will outline the new approaches and targets being investigated, which may provide opportunities for novel therapeutic interventions in these debilitating diseases.     

Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an increasing global health problem for which there are no effective disease-modifying therapies. COPD involves chronic inflammation of small airways and lung parenchyma, with the recruitment of inflammatory cells. This inflammatory-cell trafficking is orchestrated by multiple chemokines, so the blockade of chemokine receptors with selective antagonists might be an effective anti-inflammatory strategy in this disease. Several studies support the implication of several chemokines and their receptors in COPD, including chemokine receptors CXCR2 and CXCR3, with small-molecule receptor antagonists that are in development being potential anti-inflammatory therapies. Such a pharmacological strategy would provide a mechanism with which to inhibit leukocyte recruitment and, hence, reduce the inflammatory profile in COPD, which is currently unaffected by pharmacotherapy.     

Anti-TNF-α therapies in chronic obstructive pulmonary diseases

Background: Chronic obstructive pulmonary disease (COPD) and asthma are chronic diseases in which inflammation of the airways leads to progressive transient airway obstruction and TNF-α plays an important pro-inflammatory role. Objective: To assess the plausibility of anti-TNF-α therapies playing an anti-inflammatory role in asthma and COPD. Methods: Scientific rationale of TNF-α targeting in asthma and COPD was assessed individually and the available data on the use of anti-TNF-α in each disease were reviewed. Results and conclusion: Anti-TNF-α therapies demonstrate different efficacies in asthma and COPD and further supportive preclinical and clinical data are needed, especially about subsets of certain diseases which could benefit the most from these therapies.