Adenosine in the airways: implications and applications

Adenosine in a signaling nucleoside eliciting many physiological responses. Elevated levels of adenosine have been found in bronchoalveolar lavage, blood and exhaled breath condensate of patients with asthma a condition characterized by chronic airway inflammation. In addition, inhaled adenosine-5'-monophosphate induces bronchoconstriction in asthmatics but not in normal subjects. Studies on animals and humans have shown that bronchoconstriction is most likely due to the release of inflammatory mediators from mast cells. However a number of evidences suggest that adenosine modulates the function of many other cells involved in airway inflammation such as neutrophils, eosinophils, lymphocytes and macrophages. Although this clear pro-inflammatory role in the airways, adenosine may activate also protective mechanisms particularly against lung injury. For many years this dual role of adenosine in the respiratory system has represented an enigma, and only recently it has become clear that biological functions of adenosine are mediated by four distinct subtypes of receptors (A1, A2A, A2B, and A3) and that biological responses are determined by the different pattern of receptors distribution in specific cells. Therefore, pharmacological modulation of adenosine receptors, particularly A2B, may represent a novel therapeutic approach for inflammatory diseases. Moreover, as bronchial response to adenosine strictly reflects airway inflammation in asthma, bronchial challenge with adenosine is considered a valuable clinical tool to monitor airway inflammation, to follow the response to anti-inflammatory treatments and to help in the diagnostic discrimination between asthma and chronic obstructive lung disease.     

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.     

Increase in the expression of matrix metalloproteinase-12 in the airways of rats with allergic bronchial asthma

Although an involvement of matrix metalloproteinase (MMP)-12 in the development of chronic obstructive pulmonary disease (COPD) and airway inflammation has been suggested, its detailed role in the airways is not well known now. In the present study, the changes in the expression and localization of MMP-12 in airways of repeatedly antigen-challenged rats were investigated to show an association of MMP-12 with allergic bronchial asthma. Rats sensitized by dinitrophenylated Ascaris antigen were 3 times repeatedly challenged with aerosolized antigen solution to induce an asthmatic reaction. Twenty-four hours after the last antigen challenge, marked airway inflammation and bronchial smooth muscle hyperresponsiveness were observed. In this animal model of allergic bronchial asthma, a significant increase in the expression/activity of MMP-12 was found: the peak was observed at 12 h after the last antigen challenge. Furthermore, mRNA expression of MMP-12 was also increased at the early phase (1-3 h) after the last antigen challenge. Immunohistochemical studies revealed that MMP-12 was mainly expressed in airway epithelia and alveolar macrophages. These findings suggest that MMP-12 is upregulated after the induction of asthmatic reaction. MMP-12 might be a new target for the therapy against allergic bronchial asthma.     

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.     

Adenosine signalling in airways

Current research endeavours indicate that adenosine elicits strong inflammatory responses in the lung and might be involved in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and chronic obstructive pulmonary disease (COPD). The contribution of adenosine-associated effector mechanisms to the initiation, persistence and progression of the inflammatory response is highly heterogeneous and is dictated by the expression pattern of four different adenosine receptors. Selective activation or blockade of these sites can therefore be exploited in an attempt to generate novel therapies for asthma and COPD. In addition, an important development is the use of adenosine (or AMP) as a diagnostic test for discriminating asthma from COPD, and as an accurate biomarker to monitor corticosteroid requirements in asthma. It is likely that therapies interfering with adenosine signalling in the airways will offer a considerable advance in the management of asthma and COPD.     

Tachykinin receptor antagonists: potential in airways diseases.

Several lines of evidence indicate a role for the tachykinin peptides in airways diseases. For instance, elevated levels of tachykinins have been recovered from the airways of patients with asthma and chronic obstructive pulmonary disease (COPD), and airway inflammation leads to an upregulation of the tachykinin NK1 and NK2 receptors. Recent advances in tachykinin receptor pharmacology have allowed a more detailed analysis of this system and preclinical animal studies have indicated a role for the NK1 and NK2 receptors in bronchoconstriction, airway hyperresponsiveness and airway inflammation caused by allergic and nonallergic stimuli. In the past three years, work has entered the clinic and selective or dual-selective NK1/NK2 receptor antagonists appear to have the potential to affect the different aspects of asthma and COPD.     

Small airways: an important but neglected target in the treatment of obstructive airway diseases

Changes in the structure and function of the small airways (<2mm diameter) are now recognized to play a major role in airflow limitation in both chronic obstructive pulmonary disease (COPD) and severe asthma. Increased thickness of the small airway wall causes lumenal narrowing, which can be further occluded by mucus and/or inflammatory cell exudate. This leads to increased peripheral resistance, air trapping and shortness of breath on exertion. Studies in animal models and in subjects with COPD have suggested that oxidant-driven transforming growth factor (TGF)-beta1 activation and subsequent increased airway wall collagen synthesis might be central to the changes in small airway structure. However, it remains difficult to measure small airway function in patients, and delivery of inhaled drugs to peripheral airways has not yet been optimised. The increased understanding of the processes underlying the development of small airways disease should facilitate pharmacological intervention targeted at this hitherto neglected compartment.     

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.     

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.     

Airway hyperresponsiveness: using bronchial challenge tests in research and management of asthma.

Bronchial challenge tests have been standardized in detail during the past two decades. They are providing relevant pathophysiological and clinical information about patients with asthma or chronic obstructive pulmonary disease (COPD), by allowing the measurement of the degree of airway hyperresponsiveness, which includes an increased sensitivity as well as increased maximal response to bronchoconstrictor stimuli. There are various types of challenges, to which the responses are not interchangeable. Responses to so-called "indirect" challenges are largely dependent on the state of activation of inflammatory or resident cells within the airways, and the state of activation can vary rapidly, either spontaneously or through intervention. Responses to "direct" challenges are dependent on less variable, rather chronic features of airways inflammation or remodeling. Bronchoprovocation tests provide integrated information about multiple pathophysiological pathways within the airway. This is in contrast to the measurements of cells, mediators, or cytokines in biological fluids, which provide only very specific information on selected inflammatory pathways. It has recently been shown that the outcome of asthma can substantially be improved when long-term treatment is not only guided by symptoms and lung function, but also by the degree of airway hyperresponsiveness to direct stimuli. Taken together, current data warrant a broader usage of bronchoprovocation tests in the research as well as clinical management of asthma and COPD. In asthma, it allows selective, individually targeted therapy of the patient as opposed to the currently recommended regimens that are (increasingly) unselective in their approach. The potential benefits of monitoring other phenotypic disease markers is currently under investigation.     

Etanercept for refractory asthma therapy

Asthma is a chronic disease of the airways in which inflammation causes bronchial hyper-reactivity and consequent asthma attacks triggered by various stimuli. The bronchospasm attacks are usually relieved by short-acting beta2 agonists, and inflammation and bronchial hyper-reactivity are reduced by maintenance therapy and, in particular, by inhaled corticosteroids. In milder asthma subjects, airway inflammation is dominated by eosinophils, whereas in more severe asthma increased neutrophil counts were detected. In severe/refractory asthma, TNF-alpha is known to play a role in the maintenance of neutrophilic inflammation and of bronchial hyper-responsiveness and is not influenced by corticosteroid therapy. Etanercept, a TNF-alpha-blocking agent, could represent one of the potential therapies for refractory asthma based on demonstrated safety and efficacy.     

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.     

Arginase: a key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives

Allergic asthma is a chronic inflammatory airways'' disease, characterized by allergen-induced early and late bronchial obstructive reactions, airway hyperresponsiveness (AHR), airway inflammation and airway remodelling. Recent ex vivo and in vivo studies in animal models and asthmatic patients have indicated that arginase may play a central role in all these features. Thus, increased arginase activity in the airways induces reduced bioavailability of L-arginine to constitutive (cNOS) and inducible (iNOS) nitric oxide synthases, causing a deficiency of bronchodilating and anti-inflammatory NO, as well as increased formation of peroxynitrite, which may be involved in allergen-induced airways obstruction, AHR and inflammation. In addition, both via reduced NO production and enhanced synthesis of L-ornithine, increased arginase activity may be involved in airway remodelling by promoting cell proliferation and collagen deposition in the airway wall. Therefore, arginase inhibitors may have therapeutic potential in the treatment of acute and chronic asthma. This review focuses on the pathophysiological role of arginase in allergic asthma and the emerging effectiveness of arginase inhibitors in the treatment of this disease.     

Etanercept for refractory asthma therapy

Asthma is a chronic disease of the airways in which inflammation causes bronchial hyper-reactivity and consequent asthma attacks triggered by various stimuli. The bronchospasm attacks are usually relieved by short-acting β₂ agonists, and inflammation and bronchial hyper-reactivity are reduced by maintenance therapy and, in particular, by inhaled corticosteroids. In milder asthma subjects, airway inflammation is dominated by eosinophils, whereas in more severe asthma increased neutrophil counts were detected. In severe/refractory asthma, TNF-α is known to play a role in the maintenance of neutrophilic inflammation and of bronchial hyper-responsiveness and is not influenced by corticosteroid therapy. Etanercept, a TNF-α-blocking agent, could represent one of the potential therapies for refractory asthma based on demonstrated safety and efficacy.     

Extending the understanding of sensory neuropeptides

The tachykinins substance P and neurokinin A are present in human airways, in sensory nerves and immune cells. Tachykinins can be recovered from the airways after inhalation of ozone, cigarette smoke or allergen. They interact in the airways with tachykinin NK1, NK2 and NK3 receptors to cause bronchoconstriction, plasma protein extravasation, and mucus secretion and to attract and activate immune cells. In preclinical studies they have been implicated in the pathophysiology of asthma and chronic obstructive pulmonary disease, including allergen- and cigarette smoke induced airway inflammation and bronchial hyperresponsiveness and mucus secretion. Dual NK1/NK2 or triple NK1/NK2/NK3 tachykinin receptor antagonists offer therapeutic potential in airway diseases such as asthma and chronic obstructive pulmonary disease.     

Bronchial hyperresponsiveness: too complex to be useful?

Measures of bronchial responsiveness are widely used for the diagnosis and monitoring of asthma. A vast array of non-specific bronchoconstrictor stimuli is available. Methacholine and histamine cause airflow limitation predominantly through a direct effect on airway smooth muscle. Indirect challenges (adenosine, exercise and hypertonic saline) induce airflow limitation by an action on cells other than smooth muscle cells, with a variety of cells, mediators and receptors being involved in this process. Bronchial responsiveness to a direct stimulus is only weakly related to airway inflammation, whereas indirect airway challenges might better reflect active airway inflammation. Both direct and indirect airway challenges are useful outcome parameters in clinical studies of asthma. For example, an indirect challenge responds to treatment with inhaled steroids within hours to days, whereas improvement in direct responsiveness might take months to years. Bronchial challenges are also an essential step in the development of new anti-asthma treatments, such as adenosine or tachykinin receptor antagonists.     

The role of neurotrophins in bronchial asthma.

Allergic bronchial asthma is characterized by chronic inflammation of the airways, development of airway hyperreactivity and recurrent reversible airway obstruction. Target and effector cells responsible for airway hyperresponsiveness and airway obstruction include sensory and motor neurons as well as epithelial and smooth muscle cells. Although it is well established that the inflammatory process is controlled by T-helper (Th) 2 cells and the Th2-derived cytokines interleukin-4, airway hyperresponsiveness-5 and interleukin-13, the mechanisms by which immune cells interact with neurons, epithelial cells or smooth muscle cells still remain uncertain. Since there is growing evidence for extensive communication between neurons and immune cells, the mechanisms of this neuro-immune crosstalk in lung and airways of asthmatic patients are recently becoming the focus of asthma research. Neurotrophins represent candidate molecules regulating and controlling this crosstalk between the immune and peripheral nervous system. They are constitutively expressed by resident lung cells and produced in increasing concentrations by immune cells invading the airways under pathological conditions. They modify the functional activity of sensory and motor neurons, leading to enhanced and altered neuropeptide and tachykinin production. These effects are defined as "neuronal plasticity". The consequences are the development of "neurogenic inflammation" due to neuropeptide and tachykinin activities.     

Biology of the interleukin-9 pathway and its therapeutic potential for the treatment of asthma

Asthma is a complex disease characterized by variable airflow limitation, hyperresponsiveness, and airways inflammation. Despite valuable therapeutic advances to control asthma symptoms in the last decade, a quantifiable proportion of patients with moderate to severe asthma continue to experience inadequate disease control, highlighting an important unmet need. In animal models of asthma, interleukin (IL)-9 regulates the development of airway inflammation, mucus production, airway hyperresponsiveness, and airway fibrosis largely by increasing mast cell numbers and activity in the airways. Mast cells are involved in the pathogenesis of eosinophilic and noneosinophilic asthma. Thus, targeting the IL-9 pathway may provide a new therapeutic modality for asthma. The purpose of this review is to summarize the IL-9-mast cell axis in the pathogenesis of asthma and discuss clinical studies with a humanized anti-IL-9 monoclonal antibody, MEDI-528, in subjects with asthma.     

Inhibitory effect of Platycodi Radix on ovalbumin-induced airway inflammation in a murine model of asthma

Asthma is a chronic inflammatory disease of the airways characterized by an associated increase in airway responsiveness. In this study, we investigated the inhibitory effect of an aqueous extract from the root of Platycodi Radix (Changkil: CK) on airway inflammation in a murine model of asthma. Mice were sensitized and challenged by ovalbumin (OVA) inhalation to induce chronic airway inflammation and airway remodeling. CK markedly decreased the number of infiltrated inflammatory cells and the levels of Th1 and Th2 cytokines and chemokines compared with those in the OVA-induced group. In addition, CK reduced OVA-specific IgE levels in bronchoalveolar lavage (BAL) fluid. Based on lung histopathological studies, inflammatory cell infiltration and mucus hypersecretion were inhibited by CK administration compared to that in the OVA-induced group. Lung weight was reduced after CK administration. Also, increased generation of ROS in BAL fluid, as well as NF-κB nuclear translocation, by inhalation of OVA was diminished by CK. Moreover, CK reduced the OVA-induced upregulation of matrix metalloproteases activity. These findings indicate that oxidative stress may play a crucial role in the pathogenesis of bronchial asthma induced by OVA and that CK may be useful as an adjuvant therapy for the treatment of bronchial asthma.     

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.