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.     

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.     

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.     

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.     

Emerging drugs for asthma

INTRODUCTION: Current drug treatments for asthma relieve bronchospasm and airway inflammation but do not offer a cure, and symptoms return when treatment is stopped. Asthma management guidelines emphasize the importance of effective asthma treatment to achieve and maintain asthma control. However, despite widely available and effective treatments, achieving asthma control is still an unmet need for many patients. AREAS COVERED: Remarkable efforts have been made to identify the characteristic features of difficult-to-control (usually severe) asthma that are different from those described for mild-to-moderate asthma, setting the stage for the development of new and even individualized therapies. The most fascinating options of the new asthma treatments are biologic therapies, in particular monoclonal antibodies. In addition, some novel once-daily combinations of long-acting β(2)-agonist and inhaled corticosteroids are under development. EXPERT OPINION: Asthma is a complex syndrome made up of a number of disease variants or asthma phenotypes, with different underlying pathophysiology. As different drugs target different pathways, it is necessary to determine the individual profile of pathophysiological abnormalities for each patient. Several cytokines have been implicated in the inflammatory cascades leading to the different asthma phenotypes, and the most relevant ones are discussed. The challenge in treating asthma resides precisely in its heterogeneity.     

Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential

The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions are airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hypersecretion in these diseases, which are further induced by infection or components of cigarette smoke. Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease-mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF and targeted inflammatory cell delivery for controlling other chronic inflammatory lung diseases. We propose that the design and development of nano-based targeted theranostic vehicles with therapeutic, imaging and airway-defense penetrating capability, will be invaluable for treating chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease.     

Exacerbations of asthma and chronic obstructive pulmonary disease (COPD): focus on virus induced exacerbations

Asthma and chronic obstructive pulmonary disease (COPD) are the 2 most prevalent chronic airway diseases. Much of the morbidity, mortality and health care costs of the diseases are associated with acute exacerbations, which are episodes of increased symptoms and airflow obstruction. Over the last decade evidence has emerged implicating virus respiratory tract infections as a major cause of exacerbations of both asthma and COPD. Current therapies are not very effective in the prevention or treatment of virus-induced exacerbations and exacerbations are therefore a major unmet medical need. The development of new and novel treatments requires a better understanding of the molecular and cellular mechanisms linking virus infection with exacerbations of asthma and COPD. This article provides an overview of current knowledge regarding the mechanisms of virus-induced exacerbations in both asthma and COPD. It will also review existing treatments and future treatments that are in advanced stages of development.     

Nano-based theranostics for chronic obstructive lung diseases: challenges and therapeutic potential

The major challenges in the delivery and therapeutic efficacy of nano-delivery systems in chronic obstructive airway conditions are airway defense, severe inflammation and mucous hypersecretion. Chronic airway inflammation and mucous hypersecretion are hallmarks of chronic obstructive airway diseases, including asthma, COPD (chronic obstructive pulmonary disease) and CF (cystic fibrosis). Distinct etiologies drive inflammation and mucous hypersecretion in these diseases, which are further induced by infection or components of cigarette smoke. Controlling chronic inflammation is at the root of treatments such as corticosteroids, antibiotics or other available drugs, which pose the challenge of sustained delivery of drugs to target cells or tissues. In spite of the wide application of nano-based drug delivery systems, very few are tested to date. Targeted nanoparticle-mediated sustained drug delivery is required to control inflammatory cell chemotaxis, fibrosis, protease-mediated chronic emphysema and/or chronic lung obstruction in COPD. Moreover, targeted epithelial delivery is indispensable for correcting the underlying defects in CF and targeted inflammatory cell delivery for controlling other chronic inflammatory lung diseases. We propose that the design and development of nano-based targeted theranostic vehicles with therapeutic, imaging and airway-defense penetrating capability, will be invaluable for treating chronic obstructive lung diseases. This paper discusses a novel nano-theranostic strategy that we are currently evaluating to treat the underlying cause of CF and COPD lung disease.     

PDE4 inhibitors and chronic obstructive pulmonary disease

Inhibitors of the 3‘, 5‘ cyclic nucleotide phosphodiesterase Type IV (PDE4) are able to modulate a variety of inflammatory responses in both cell and animal based models. These results suggest that PDE4 inhibitors may provide a novel approach for treating chronic inflammatory diseases. A number of pharmaceutical companies are developing PDE4 inhibitors for the treatment of inflammatory diseases including asthma, rheumatoid arthritis, multiple sclerosis and Crohn’s disease. Recent clinical evidence suggests that PDE4 inhibitors may also be efficacious in the treatment of chronic obstructive pulmonary disease (COPD). This review will summarise current treatments for COPD, the scientific rationale for using PDE4 inhibitors to treat this disease and the current status of known PDE4 inhibitors.     

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.     

Matrix metalloproteinases in asthma and COPD

Asthma and chronic obstructive pulmonary disease (COPD) are both highly prevalent, chronic inflammatory lung diseases that lead to significant morbidity and mortality. Matrix metalloproteinases (MMPs) are extracellular matrix degrading enzymes that play a critical role in normal development and physiological tissue remodeling and repair. In addition, they play an important role in the regulation of the kinetics and function of inflammatory cells. There is increasing evidence that MMPs are involved in the pathogenesis of both asthma and COPD, and several MMPs are possible therapeutic targets in these common chronic airway diseases.     

肺内吸入给药治疗哮喘和慢性阻塞性肺病研究进展

哮喘和慢性阻塞性肺疾病(COPD)是最常见的呼吸道疾病之一,全球分别有3 亿和2.1 亿患者。肺部吸入给药是治疗和管理哮喘、COPD 等呼吸道疾病的首选给药方式,而患者的依从性与该类制剂的疗效优劣有密切关系。综述现在已经上市的肺部吸入给药治疗哮喘和慢性阻塞性肺疾病的主要剂型和药品,以及雾化吸入剂、定量吸入剂和干粉吸入剂对患者依从性的影响,并认为提高患者依从性需要反复提供给患者个性化用药和正确使用给药装置的指导。     

Pharmacology of airway irritability

Bronchial hyperresponsiveness is a characteristic feature of respiratory diseases of the lung, including asthma and chronic obstructive pulmonary disease (COPD). However, asthmatic subjects respond to a range of physiological and chemical insults that are otherwise innocuous in healthy subjects or in patients with COPD, suggesting that the mechanisms underlying this phenomenon are characteristic of the asthma phenotype. Increasingly, there is evidence of a role for airway nerves in irritable airways and pharmacological targeting of the pathways involved may lead to the development of novel treatments for this disease. In this context, the recent cloning of the vanilloid receptor may be a useful target for drug discovery in respiratory disease.     

Interleukin-9 as a possible therapeutic target in both asthma and chronic obstructive airways disease

Asthma and chronic obstructive pulmonary disease (COPD) are important causes of morbidity and mortality worldwide. Both asthma and COPD are characterized by airflow limitation but distinct differences occur in the pulmonary inflammatory responses in the two conditions. Treatment options for asthma and COPD are limited (especially so for COPD), and both are in need of novel therapeutic interventions. Interleukin-9 (IL-9) is a potential target for such a therapy. This Th2-type cytokine, is secreted by a number of different cell types, and has multiple effects on a wide range of cells within the lung. In this review we will summarize current knowledge about the immunobiology of IL-9 and discuss the role played by IL-9 in inflammation in both asthma and COPD, and its potential as a therapeutic target.     

Beta2-adrenoceptor polymorphisms and obstructive airway diseases: important issues of study design

1. Asthma and chronic obstructive pulmonary disease (COPD) are chronic airway diseases characterized by airflow obstruction. The beta(2)-adrenoceptor mediates bronchodilatation in response to exogenous and endogenous beta-adrenoceptor agonists. 2. Single nucleotide polymorphisms in the beta(2)-adrenoceptor gene (ADRB2) cause amino acid changes (e.g. Arg16Gly, Gln27Glu) that potentially alter receptor function. Recently, a large cohort study found no association between asthma susceptibility and beta(2)-adrenoceptor polymorphisms. In contrast, asthma phenotypes, such as asthma severity and bronchial hyperresponsiveness, have been associated with beta(2)-adrenoceptor polymorphisms. Of importance to asthma management, coding region polymorphisms may alter the response to short-acting and long-acting beta-adrenoceptor agonists, which are commonly prescribed asthma treatments. 3. Optimizing study design would enhance the robustness of genetic association studies of ADRB2 polymorphisms in airway diseases. Characteristics of high-quality studies include suitable study design and subject selection, optimal study of polymorphisms and haplotypes, disease outcomes of relevance, adequate sample size, adjustment for confounding factors, supportive functional data and appropriate analysis, interpretation and replication. Enhancing these study design factors will provide high-quality evidence regarding the biological and clinical importance of beta(2)-adrenoceptor pharmacogenomics in asthma and COPD.     

Airway nitrergic pathways: is there therapeutic potential in asthma and COPD?

Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterised by airway hyperresponsiveness, epithelial damage, oxidative stress and airway inflammation. Inflammatory cells, including macrophages, neutrophils, eosinophils and lymphocytes, are crucial in the pathogenesis of asthma and COPD. The prevalence of asthma and COPD is increasing, especially in Western countries. Symptomatic treatment is based on reduction of airway obstruction by inhalation of beta(2)-receptor agonists and attenuation of the underlying inflammatory reactions by inhalation of corticosteroids. Because these agents only suppress symptoms, there is a need for medicines that remove the cause of these airway diseases.     

Estrogen as a new therapeutic target for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) affect the lives of a large portion of the population and can lead to morbidity and mortality. In many women, the incidence and severity of asthma exacerbations vary along their menstrual cycle. Estrogen, a natural occurring hormone, affects differently many of the cell types that are involved in asthma, including macrophages, eosinophils, neutrophils, lymphocyte, mast cells, fibroblasts, epithelial and smooth muscle cells. By binding to its receptors on the plasma or nuclear membrane, estrogen affects the expression of a plethora of proteins that are involved in the pathogenesis of asthma and COPD. In this review we will summarize the current knowledge of the role of estrogen in the expression, production and secretion of inflammatory agents that are involved in asthma and COPD and its potential therapeutic role in these diseases.     

Agents against cytokine synthesis or receptors

Various cytokines play a critical role in pathophysiology of chronic inflammatory lung diseases including asthma and chronic obstructive pulmonary disease (COPD). The increasing evidence of the involvement of these cytokines in the development of airway inflammation raises the possibility that these cytokines may become the novel promising therapeutic targets. Studies concerning the inhibition of interleukin (IL)-4 have been discontinued despite promising early results in asthma. Although blocking antibody against IL-5 markedly reduces the infiltration of eosinophils in peripheral blood and airway, it does not seem to be effective in symptomatic asthma, while blocking IL-13 might be more effective. On the contrary, anti-inflammatory cytokines themselves such as IL-10, IL-12, IL-18, IL-23 and interferon-gamma may have a therapeutic potential. Inhibition of TNF-alpha may also be useful in severe asthma or COPD. Many chemokines are also involved in the inflammatory response of asthma and COPD through the recruitment of inflammatory cells. Several small molecule inhibitors of chemokine receptors are now in development for the treatment of asthma and COPD. Antibodies that block IL-8 reduce neutrophilic inflammation. Chemokine CC3 receptor antagonists, which block eosinophil chemotaxis, are now in clinical development for asthma therapy. As many cytokines are involved in the pathophysiology of inflammatory lung diseases, inhibitory agents of the synthesis of multiple cytokines may be more useful tools. Several such agents are now in clinical development.     

PDE4 inhibition: a novel approach for the treatment of inflammatory bowel disease

Inflammation is a hallmark of inflammatory bowel disease (IBD), and elevation of cAMP levels can inhibit the pro-inflammatory and tissue-destructive properties of leukocytes. Phosphodiesterase 4 (PDE4) is the predominant enzyme that metabolizes cAMP in inflammatory cells, and the anti-inflammatory and immunomodulatory potential of PDE4 inhibitors in human leukocytes, endothelium and epithelium is well documented. Although PDE4 inhibitors have been investigated as treatments for several inflammatory diseases, this has focused mainly on asthma and chronic obstructive disease (COPD). Historically, their clinical utility has been limited by nausea and emesis. However, the PDE4 inhibitors cilomilast and roflumilast have recently shown efficacy in asthma and COPD, with a reduced propensity to cause nausea and emesis. In this review, we summarize for the first time the evidence that PDE4 inhibitors might have therapeutic benefit in IBD, and discuss mechanisms of action beyond the inhibition of inflammatory cells.