Effects of inhaled corticosteroids, leukotriene receptor antagonists, or both, plus long-acting beta2-agonists on asthma pathophysiology: a review of the evidence

Chronic inflammation and smooth muscle dysfunction are consistent features of asthma, and are responsible for disease progression and airway remodelling. The development of chronic airway inflammation depends upon the recruitment and activation of inflammatory cells and the subsequent release of inflammatory mediators, including cytokines. Cellular and histological evaluation of drugs with anti-inflammatory activity, such as inhaled corticosteroids (ICSs), is achieved by analysing samples of lung tissue or biological fluids, obtained by techniques such as bronchial biopsy, bronchoalveolar lavage and sputum induction. These provide valuable information on the inflammatory processes occurring in the lung, although not all are equal in value. The beneficial effects of ICSs in asthma treatment are a consequence of their potent and broad anti-inflammatory properties. Furthermore, there have been promising results indicating that ICSs can reverse some of the structural changes that contribute to airway remodelling. Long-acting beta2-agonists (LABAs) added to ICSs provide greater clinical efficacy than ICSs alone, suggesting the possibility of complementary activity on the pathophysiological mechanisms of asthma: inflammation and smooth muscle dysfunction. Leukotrienes play a part in the pathogenesis of asthma. Leukotriene receptor antagonists (LTRAs) directly inhibit bronchoconstriction and may have some anti-inflammatory effects, although the extent to which inhibiting one set of inflammatory mediators attenuates the inflammatory response is questionable. In concert with their effect on a broad variety of inflammatory mediators and cells, treatment with ICSs (including ICSs and LABAs) results in superior control of the pathophysiology of asthma and superior clinical efficacy as assessed by the greater improvements in pulmonary function and overall control of asthma compared with LTRAs.     

Putative mediator role of endothelin-1 in asthma and other lung diseases

1. There is an increasing amount of research to implicate endothelin (ET)-1, a member of a family of 21 amino acid peptides, as a potentially important mediator in pulmonary diseases, in particular asthma and pulmonary hypertension. Thus, ET-1 fits several of the standard criteria that need to be fulfilled for a pathophysiologically relevant substance. 2. Endothelin-1 is present in abundance in human lung: the major loci for ET-1 are the epithelium, endothelium, endocrine cells and inflammatory cells. Furthermore, the receptors that mediate the biological effects of ET-1, the ETA and ETB receptor subtypes, are found in human lung, predominantly in airway smooth muscle, and vascular smooth muscle and, to a lesser extent, nerves. There is no change in the relative proportions of ETA and ETB receptors in asthmatic versus non-asthmatic bronchial smooth muscle and peripheral lung. 3. Several studies have shown that ET-1 mimics several of the features of asthma (including bronchospasm, airway remodelling, inflammatory cell recruitment and activation, oedema, mucus secretion, airway hyperreactivity and dysfunction in neuronal inputs); however, some other reports are at odds with these findings. 4. Endothelin-1 mimics the two classical features of pulmonary hypertension (pulmonary vascular constriction and remodelling), which is often a serious complication of chronic obstructive pulmonary disease. 5. Intranasal ET-1 produces several of the symptoms of allergic rhinitis. 6. There are several reports of increased levels and/or expression of ET in patients with many pulmonary disorders, in particular asthma or pulmonary hypertension, with some evidence of a correlation between ET amounts and disease severity; however, other studies do not confirm these observations. 7. Despite these intriguing data in support of a pathophysiological role of ET-1 in lung disease, the definitive test and most difficult criteria to fulfil, the clinical evaluation of ET receptor antagonists or ET synthesis inhibitors, has still to be conducted. Only after these pivotal data are available will we be able to determine definitively whether ET-1 is a pathophysiologically important mediator in lung diseases or merely an interesting peptide with several effects in the pulmonary system.     

以趋化因子受体为靶点的抗哮喘小分子药物研究进展

哮喘是一种以气道炎症、气道高反应性及气道重塑为特征并伴随支气管炎性细胞浸润的慢性呼吸道疾病。趋化因子通过与趋化因子受体结合介导炎性细胞向支气管迁移,在哮喘发病中起着重要的作用。以趋化因子及其受体为靶点是目前抗炎、抗哮喘药物研究的热点。本文主要针对近年来趋化因子受体的小分子拮抗剂在抗哮喘方面的研究成果予以综述,将有助于抗哮喘药物设计,为进一步研究提供参考。     

Leukotriene inhibitors and non-steroidal therapies in the treatment of asthma

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulair?, Merck) and zafirlukast (Accolate?, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflo?, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.     

Leukotriene inhibitors and non-steroidal therapies in the treatment of asthma

Asthma is the most common chronic disease of childhood whose morbidity and mortality continues to rise [1]. Drugs used in the treatment of asthma must be targeted at reversing three principle pathophysiologic features: bronchoconstriction, mucus plugging/hypersecretion and inflammation. In the past two decades, the contribution of airway inflammation to the development and progression of asthma symptoms and airway pathology has become a critical focus. Chronic airway inflammation can lead to the progressive decline and irreversible loss of lung function and airway remodelling [2]. In recent years, therapies aimed at diminishing airway inflammation have been at the forefront of asthma management. Steroids have been extensively studied and used as primary anti-inflammatory agents in the management of the asthmatic patient with persistent symptoms of varying severity. Within the last decade, however, several additional non-steroidal classes of drugs have begun to emerge as anti-inflammatory agents for the treatment of asthma. This article will focus on these non-steroidal drugs which have been developed and investigated within the last 5 years. Particular emphasis will be placed on leukotriene receptor antagonists, but anti-IgE and anti-IL-4 therapies, as well as phosphodiesterase inhibitors will also be discussed. Of these new therapies, only two leukotriene receptor antagonists, montelukast (Singulairtrade mark, Merck) and zafirlukast (Accolatetrade mark, AstraZeneca) and the 5-lipoxygenase inhibitor, zileuton (Zyflotrade mark, Abbott Laboratories), have been recommended, approved and are currently available for use in the treatment of paediatric patients with asthma in the United States.     

Nerve growth factor and its receptors in asthma and inflammation

Nerve growth factor (NGF) is a high molecular weight peptide that belongs to the neurotrophin family. It is synthesized by various structural and inflammatory cells and activates two types of receptors, the TrkA (tropomyosin-receptor kinase A) receptor and the p75^NTR receptor, in the death receptor family. NGF was first studied for its essential role in neuronal growth and survival. Recent reports indicate that it may also help mediate inflammation, especially in the airways. Several studies in animals have reported that NGF may induce bronchial hyperresponsiveness, an important feature of asthma, by increasing sensory innervation. It may also induce migration and activation of inflammatory cells, which infiltrate the bronchial mucosa, and of structural cells, including epithelial, smooth muscle cells and pulmonary fibroblasts. Increased NGF expression and release is observed in asthma patients after bronchial provocation with allergen. Taken together, the data from the literature suggest that NGF may play a role in inflammation, bronchial hyperresponsiveness and airway remodelling in asthma and may help us to understand the neuro-immune cross-talk involved in chronic inflammatory airway diseases.     

白三烯受体拮抗剂研究新进展

白三烯(leukotrienes,LTs)是花生四烯酸的代谢产物之一,是白细胞重要的趋化剂和激动剂,是哮喘发病机制中最重要的炎症介质之一。可引起气道平滑肌收缩,增加血管通透性,增加黏液分泌,促进炎症细胞如嗜酸性粒细胞在气道的聚集,并能促进气道结构细胞的增殖从而参与气道重塑。白三烯受体拮抗剂能在一定程度上影响和克服这些病理生理变化,从而达到控制哮喘的目的,其在哮喘治疗中的作用日益受到人们重视。本文综述白三烯在哮喘发病机制中的作用和有关受体拮抗剂的新进展。     

Vascular remodelling and angiogenesis in asthma: morphological aspects and pharmacological modulation

Tissue remodelling can affect the entire bronchial wall, including the vascular component of the mucosa, in bronchial asthma. The bronchial mucosa is more vascularized in asthmatic patients than in healthy subjects, showing an increase in the number and dimension of vessels and vascular area. In addition, vascular changes can contribute to obstructing the airway flow in asthma. Vascular Endothelial Growth Factor, a mediator derived from endothelial cells, but also from most inflammatory cells in asthma, plays a primary role in vascular remodelling and angiogenesis. Studies on lung biopsies showed that anti-asthma drugs can decrease to varying degrees the vascular component of airway remodelling in asthma. Among asthma medications, inhaled corticosteroids effectively reverse all aspects of vascular remodelling such as vasodilatation, increased vascular permeability and angiogenesis. A better knowledge of angiogenetic mechanisms in asthma will support the selection of specific medications acting on this aspect of airway remodelling. The aim of this review is to analyze the morphological aspects of the vascular component in airway remodelling in asthma, as well as its pharmacological modulation.     

Emerging role of long acting muscarinic antagonists for asthma

Acetlycholine is involved in the control of airway smooth muscle constriction and in recruitment of inflammatory cells via neuronal and paracrine effects on muscarinic type 3 receptors. Long acting muscarinic antagonists (LAMA) are well established in guidelines for COPD but are not currently licensed for use in asthma. There are emerging data from key clinical trials to show that LAMA may confer bronchodilator effects and improved control when used in addition to inhaled corticosteroid (ICS) alone or in conjunction with long acting β-adrenoceptor agonists (LABA). Further studies in persistent asthmatic patients are required to evaluate ICS sparing effects of LAMA looking particularly at airway hyper-responsiveness and surrogate inflammatory markers, in addition to evaluation of possible synergy between LAMA and LABA when given together. Future possible development of combination inhalers comprising ICS/LAMA or ICS/LAMA/LABA will require long term studies looking at asthma control and exacerbations in both adult and paediatric patients.     

Emerging drugs for asthma

Background: Current therapies for asthma are aimed at controlling disease symptoms and for the majority of asthmatics inhaled corticosteroid anti-inflammatory therapy is effective. However, this approach requires life-time therapy while a subset of patients remains symptomatic despite optimal treatment creating a clear unmet medical need. Objectives: It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches may identify new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach may provide disease-modifying treatments. Results: Significant areas of drug development include humanised monoclonal antibodies (mAb) for asthma therapy including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs. Small-molecule receptor antagonists also target receptors or the cellular signal transduction pathways that are activated following cytokine or chemokine receptor ligation. Another approach is to target asthma relevant mediators or the pathways controlling pro-inflammatory leukocyte accumulation within the asthmatic lung. Conclusions: This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy. Current therapies for asthma are aimed at controlling disease symptoms, and for the majority of asthmatics inhaled corticosteroid anti-inflammatory therapy is effective. However, this approach requires lifetime therapy; and a subset of patients remains symptomatic despite optimal treatment, creating a clear unmet medical need. It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches may identify new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach may provide disease-modifying treatments. Significant areas of drug development include humanised mAb for asthma therapy, including those against IgE, IL-4 and IL-5. Asthma-relevant cytokines or chemokines have been targeted in a number of other ways. These include the use of humanised receptor blocking mAb or the removal of cytokines or chemokines via their binding to soluble receptor constructs. Small-molecule receptor antagonists also target receptors or the cellular signal transduction pathways that are activated following cytokine or chemokine receptor ligation. Another approach is to target asthma-relevant mediators, or the pathways controlling pro-inflammatory leukocyte accumulation within the asthmatic lung. This review will discuss the current status, therapeutic potential and potential problems of these novel drug developments in asthma therapy.     

Individual cytokines contributing to asthma pathophysiology: valid targets for asthma therapy?

Asthma is a common, chronic inflammatory condition of the airways that leads to airway hyperresponsiveness, reversible narrowing of the airways, and airway wall remodeling. Cytokines are involved in various aspects of asthma pathophysiology, such as the polarization of T-helper (Th)2 cells, antigen presentation, immunoglobulin (Ig)E response, airway wall remodeling, and mast cell and eosinophil recruitment and activation. Th2-derived cytokines, such as interleukin (IL)-4, IL-5 and IL-13 contribute to many of these aspects. Inhibition of individual cytokines for asthma therapy has been, and continues to be investigated. Anti-IL-5 monoclonal antibodies did not demonstrate beneficial effects in asthma, with only partial inhibition of eosinophilia in the airway wall; soluble IL-4 receptor, which neutralizes the effects of IL-4, has provided modest improvements in moderate asthma. The anti-IgE monoclonal antibody approach has demonstrated the most benefit in allergic asthma, particularly in severe disease. Which individual cytokine target can be inhibited with beneficial effects comparable to or above that of current inhaled corticosteroids can only be discovered through clinical trials. Blocking the effects of more than one cytokine may be more successful, and greater therapeutic effects may be observed in particular categories of asthma.     

Rho kinase inhibitors: a novel therapeutical intervention in asthma?

In asthma, inflammatory mediators that are released in the airways by recruited inflammatory cells and by resident structural cells result in airway hyperresponsiveness caused by increased bronchoconstriction. In addition, chronic inflammation appears to drive remodelling of the airways that contributes to the development of fixed airway obstruction and airway hyperresponsiveness in chronic asthma. Airway remodelling includes several key features such as excessive deposition of extracellular matrix proteins in the airway wall (fibrosis) and increased abundance of contractile airway smooth muscle encircling the airways. Current asthma therapy fails to inhibit these features satisfactorily. This review focuses on Rho kinase as a potential drug target in asthma, as compelling evidence from animal models and ex vivo studies suggests a central role for this enzyme and its associated signalling in acute and chronic airway hyperresponsiveness.     

The role of antileukotrienes in the treatment of asthma

Cysteinyl leukotrienes (Cys-LTs) are mediators released in asthma and are both direct bronchoconstrictors and proinflammatory substances that mediated several steps in the pathophysiology of chronic asthma, including inflammatory cells recruitment, vascular leakage, and possibly airway remodelling. Available evidence from clinical trials and real world experience derived from managing patients with asthma justifies a broader role for antiLTRAs in asthma management than that recommended in the National Asthma Education and Prevention Programm (NAEPP) and National Health Lung and Blood Institute (NHLBI) treatment guidelines. Leukotriene-receptor antagonist drugs (LTRAs) seem to be effective alternatives to inhaled corticosteroids (ICS) either as monotherapy or as adjunctive therapy that reduces the need for higher doses of ICS in patients with mild-to-moderate persistent asthma. LTRAs may be used as adjunctive therapy for al levels of disease severity because they are effective in combination with ICS during long-term maintenance therapy. The agents seem especially effective in preventing aspirin-induced asthma, exercise-induced asthma (EIA) and they may provide an additional advantage of reducing nasal congestion in patients with both asthma and rhinitis.     

The treatment targets of asthma: from laboratory to clinic

Asthma is a chronic disease characterised by airways hyperresponsiveness, airways inflammation, airways remodelling and reversible airways obstruction. Airway structural cells, recruited inflammatory cells and many mediators such as cytokines, chemokines and adhesion molecules are involved in the pathogenesis of asthma. Although asthma is treatable in most, but not all patients by currently available drugs, no treatment is preventive or curative and the disease has reached epidemic proportions worldwide and its incidence is continuing to increase. Many thousands have chronic, severe asthma and suffer daily symptoms making it imperative that we continue to improve our understanding of the mechanisms of asthma particularly related to airway inflammation and remodelling, the hallmarks of asthma, and to identify new therapeutic targets. In this review we will discuss current drugs and potential targets in the treatment of asthma.     

Recent developments in CCR3 antagonists

Selective eosinophil recruitment into inflammatory sites and their subsequent activation is a characteristic of allergic diseases, such as asthma, rhinitis and atopic dermatitis. CC chemokine receptor-3 (CCR3) is the principal mediator of eosinophil chemotaxis and is expressed on a variety of inflammatory cells associated with allergic responses; these cells include basophils, mast cells and T-helper-2 lymphocytes, and resident tissue cells such as airway epithelium. Animal studies suggest that CCR3 is a prominent mediator of allergic responses and that antagonizing the receptor will lead to a reduction in airway inflammation. The potential importance of CCR3 in allergic inflammation has made this receptor a target for drug development. This review summarizes the efforts in this research area that have been reported in the last two years.     

Cells, mediators and Toll-like receptors in COPD

Chronic obstructive pulmonary disease (COPD) is a global health problem. Being a progressive disease characterized by inflammation, it deteriorates pulmonary functioning. Research has focused on airway inflammation, oxidative stress, and remodelling of the airways. Macrophages, neutrophils and T cells are thought to be important key players. A number of new research topics received special attention in the last years. The combined use of inhaled corticosteroids and long-acting β₂-adrenoceptor agonists produces better control of symptoms and lung function than that of the use of either compound alone. Furthermore, collagen breakdown products might be involved in the recruitment and activation of inflammatory cells by which the process of airway remodelling becomes self-sustaining. Also, TLR (Toll-like receptor)-based signalling pathways seem to be involved in the pathogenesis of COPD. These new findings may lead to new therapeutic strategies to stop the process of inflammation and self-destruction in the airways of COPD patients.     

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.     

Role of inflammatory mediators in asthma.

Release of inflammatory mediators such as histamine and products of arachidonic acid metabolism has been demonstrated in bronchoalveolar lavage fluid of patients with asthma. Their precise cellular source is not clear but many cells types such as eosinophils, macrophages and mast cells may contribute to the generation of a wide variety of chemical mediators. These can mimic many of the features associated with asthma including bronchoconstriction, bronchial hyperresponsiveness and airway microvascular leakage. Development of specific mediator receptor antagonists or inhibitors of mediator synthesis may clarify the role of particular inflammatory mediators such as the sulphidopeptide leukotrienes or platelet-activating factor in asthma. It seems unlikely that only one particular mediator is responsible for all the manifestations of asthma.     

Cysteinyl leukotriene receptors

Cysteinyl leukotrienes (CysLTs) are important inflammatory mediators in asthma and allergic disorders. Two types of CysLT receptors, CysLT(1) and CysLT(2), which were originally defined pharmacologically based on their sensitivity to CysLT(1) specific antagonists, are responsible for most of the known CysLT biological actions. The regulation of CysLT receptor expression and signaling in disease processes is largely unclear. Recent molecular cloning of both receptor subtypes from several different species will greatly facilitate future research in understanding CysLT signal transduction mechanisms. Expression of the relatively better-studied CysLT(1) is verified in lung tissues and peripheral blood cells. Elucidating how this receptor mediates airway inflammation will deepen our understanding of asthma etiology. On the other hand, detection of CysLT(2) in the heart, brain, and adrenal glands will inject new excitement into the search for novel CysLT functions. This review summarizes receptor cloning, ligand binding, expression, signaling, and functions in an effort to bridge early pharmacological studies to future studies at the molecular level.