Mechanisms of acute exacerbation of respiratory symptoms in chronic obstructive pulmonary disease

Exacerbations of chronic obstructive respiratory disease (ECOPD) are acute events characterized by worsening of the patient's respiratory symptoms, particularly dyspnoea, leading to change in medical treatment and/or hospitalisation. AECOP are considered respiratory diseases, with reference to the respiratory nature of symptoms and to the involvement of airways and lung. Indeed respiratory infections and/or air pollution are the main causes of ECOPD. They cause an acute inflammation of the airways and the lung on top of the chronic inflammation that is associated with COPD. This acute inflammation is responsible of the development of acute respiratory symptoms (in these cases the term ECOPD is appropriate). However, the acute inflammation caused by infections/pollutants is almost associated with systemic inflammation, that may cause acute respiratory symptoms through decompensation of concomitant chronic diseases (eg acute heart failure, thromboembolism, etc) almost invariably associated with COPD. Most concomitant chronic diseases share with COPD not only the underlying chronic inflammation of the target organs (i.e. lungs, myocardium, vessels, adipose tissue), but also clinical manifestations like fatigue and dyspnoea. For this reason, in patients with multi‐morbidity (eg COPD with chronic heart failure and hypertension, etc), the exacerbation of respiratory symptoms may be particularly difficult to investigate, as it may be caused by exacerbation of COPD and/or ≥ comorbidity, (e.g. decompensated heart failure, arrhythmias, thromboembolisms) without necessarily involving the airways and lung. In these cases the term ECOPD is inappropriate and misleading.     

Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema

Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP- and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma.     

Diseases to differentiate from COPD, with emphasis on bronchial asthma

Differential diagnosis of chronic obstructive pulmonary disease (COPD) from asthma is not a difficult task for many clinicians. Patients with COPD have a history of heavy smoking and show a slowly progressive dyspnea on exertion and there is little variability in symptoms, and they show a poor response to bronchodilators and corticosteroids. Asthma usually begins in early childhood with atopy, shows episodic dyspnea with wheezing, especially during night and early morning. Some patients, however, show adult onset, irreversible airflow limitation, and neutrophilic airway inflammation. The airway remodeling in asthma may be the cause of confusing pathophysiology. Other diseases showing airway hyperresponsiveness, such as allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, and left heart failure presenting cardiac asthma, may sometimes show similar clinical pictures to COPD. Chronic airway diseases are also possible candidates for differential diagnosis of COPD. Bronchiectasis, sinobronchial syndrome, diffuse panbronchiolitis, obliterative bronchiolitis, and other chronic airway diseases should be considered. Some interstitial lung diseases, such as smoking-related interstitial lung diseases and lymphangioleiomyomatosis, often show obstructive ventilatory impairment, and therefore should be considered in differential diagnosis of COPD.     

TRP channels: emerging targets for respiratory disease

The mammalian transient receptor potential (TRP) superfamily of cation channels is divided into six subfamilies based on sequence homology TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPP (polycystin) and TRPML (mucolipin). The expression of these channels is especially abundant in sensory nerves, and there is increasing evidence demonstrating their existence in a broad range of cell types which are thought to play a key role in respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). These ion channels can be activated by a diverse range of chemical and physical stimuli. Physical stimuli include temperature, membrane potential changes and osmotic stress, and some of the more well known chemical stimuli include capsaicin (TRPV1), menthol (TRPM8) and acrolein (TRPA1). There is increasing evidence in this rapidly moving field to suggest that selective blockers of these channels may represent attractive novel strategies to treat characteristic features of respiratory diseases such as asthma and COPD. This review focuses on summarising the evidence that modulation of selected TRP channels may have beneficial effects at targeting key features of these respiratory diseases including airways inflammation, airways hyper-reactivity, mucus secretion and cough.     

Treatment of experimental asthma by long-term gene therapy directed against IL-4 and IL-13

The clinical manifestations of allergic asthma are believed to result from a dysregulated, T helper 2 lymphocyte (Th2)-biased response to antigen. Although asthma symptoms can be controlled acutely, there is a need for a therapy that will address the underlying immune dysfunction and provide continuous control of chronic airway inflammation. The Th2-type cytokines, IL-13 and IL-4, have been demonstrated to play a crucial role in asthma pathogenesis and their selective neutralization results in the alleviation of asthmatic symptoms in mouse models. The activity of both of these cytokines can be inhibited by a mutant IL-4 protein, IL-4 receptor antagonist (IL-4RA), and thus, continual IL-4RA therapy might be beneficial in treatment of chronic asthma. To explore the potential utility of long-term gene therapy for the treatment of asthma we used a recombinant adeno-associated virus (AAV) vector to deliver and provide sustained expression of IL-4RA in vivo. We show that AAV-mediated delivery of IL-4RA to the airways of mice reduces airway hyperresponsiveness (AHR) and airway eosinophilia triggered by either IL-13 or IL-4. Furthermore, AAV-delivered IL-4RA, expressed either systemically or in the airways of mice following allergen sensitization, significantly inhibited development of airway eosinophilia and mucus production and reduced the levels of asthma-associated Th2 cytokines and AHR in the experimental mouse model of allergic asthma. Thus, gene therapy can be a potential therapeutic option to treat and control chronic airway inflammation and asthmatic symptoms.     

A panel of multiple markers associated with chronic systemic inflammation and the risk of atherogenesis is detectable in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are both lung diseases involving chronic inflammation of the airway. The injury is reversible in asthma whereas it is mostly irreversible in COPD. Both patients of asthma and COPD are known at risk for cardiovascular disease (CVD) and type 2 diabetes (T2DM), nephropathy, and cancer. We measured multiple risk markers for atherogenesis in 55 patients with asthma and 62 patients with COPD. We wanted to know whether risk markers for atherogenesis corresponding to sequence of events of chronic inflammation were also detectable in the airway inflammatory diseases. Elevation of almost all markers involving inflammation of the endothelial cells in the coronary artery were detectable in asthma and COPD involving the inflammation of the epithelial cell lining of the airway. Both the level and % elevation of all markers were found mostly higher in COPD, the more severe form of the lung disease. We believe that these markers are useful for predicting risk of developing clinical complications such as CVD.     

Asthma and COPD: differences and similarities. With special reference to the usefulness of budesonide/formoterol in a single inhaler (Symbicort) in both diseases

Asthma and chronic obstructive pulmonary disease (COPD) both have a high prevalence worldwide and yet each condition remains underdiagnosed. Despite a number of common features, these inflammatory respiratory syndromes have distinct clinical outcomes. COPD represents a greater economic burden than asthma because it has a less favourable prognosis and is associated with greater morbidity and mortality. Therefore, it is important to distinguish between these two diseases at an early stage, so that appropriate therapy can be prescribed to prevent deterioration. However, effective treatments that may be used in both conditions can minimise the effects of misdiagnosis and maximise the impact of treatment without the associated complexity when both conditions occur together. The current review summarises the differences and similarities of asthma and COPD, in terms of risk factors, pathophysiology, symptoms and diagnosis, to provide greater understanding of the role of budesonide/formoterol in a single inhaler in both diseases.     

The cytokine network in asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are very common inflammatory diseases of the airways. They both cause airway narrowing and are increasing in incidence throughout the world, imposing enormous burdens on health care. Cytokines play a key role in orchestrating the chronic inflammation and structural changes of the respiratory tract in both asthma and COPD and have become important targets for the development of new therapeutic strategies in these diseases.     

Monoclonal antibodies for asthma and chronic obstructive pulmonary disease

Introduction: In asthma and chronic obstructive pulmonary disease (COPD), the inflammation in the airways cannot always be controlled with conventional therapies, such as inhaled corticosteroids. Addition of more specific anti-inflammatory therapies, such as monoclonal antibodies, against inflammation pathways might improve the disease outcome.

Areas covered: This review individually discusses the major inflammation pathways and their potential blocking monoclonal antibodies in asthma and COPD.

Expert opinion: The current use of omalizumab in asthma provides a good example on the potential therapeutic role of monoclonal antibodies in both asthma and COPD. There are many other monoclonal antibodies which are currently investigated as possible therapies in these diseases. The identification of the disease subsets in which such antibodies might exert the maximum benefit opens the door for personalized medicine and for targeted biological therapy in asthma and COPD.     

Effects of air pollution and smoking on chronic obstructive pulmonary disease and bronchial asthma.

Although both tobacco smoking and air pollution are believed to be environmental factors affecting the prevalence of chronic obstructive pulmonary disease (COPD) and bronchial asthma, the mechanisms by which they induce/aggravate these diseases are still not known in detail. While smoking has been demonstrated to cause and aggravate COPD and bronchial asthma, the influence of air pollution, suspected to have hazardous environmental effects since the historical episodes of severe air pollution such as the London Smog, on the prevalence of airway diseases remains unclear. This is due, in part, to changes over time in the nature of the air pollutants concerned. There have been no consistent findings on the effects on airway diseases of air pollutants at levels currently observed in developed countries. It is believed that cessation of smoking is the most important factor in preventing the development of COPD.     

Moving towards a new generation of animal models for asthma and COPD with improved clinical relevance

Asthma and chronic obstructive pulmonary disease (COPD) are complex inflammatory airway diseases characterised by airflow obstruction that remain leading causes of hospitalization and death worldwide. Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies for both conditions. In this review, we describe preclinical in vivo models that recapitulate many of the features of asthma and COPD. Specifically, we discuss the pro's and con's of the standard models and highlight recently developed systems designed to more accurately reflect the complexity of both diseases. For instance, clinically relevant allergens (i.e. house dust mite) are now being used to mimic the inflammatory changes and airway remodelling that result after chronic allergen exposures. Additionally, systems are being developed to mimic steroid-resistant and viral exacerbations of allergic inflammation - aspects of asthma where there is an acute need for new therapies. Similarly, COPD models have evolved to align with the improved clinical understanding of the factors contributing to disease progression. This includes using cigarette smoke to model not only airway inflammation and remodelling, but some systemic changes (e.g. hypertension and skeletal muscle alterations) that are thought to influence disease. Further, mouse genetics are being exploited to gain insights into the genetics of COPD susceptibility. The new models of asthma and COPD described herein demonstrate that improved clinical understanding of the diseases and better preclinical models is an iterative process that will hopefully lead to therapies that can effectively manage severe asthma and COPD.     

Obstructive lung diseases: COPD, asthma, and many imitators.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disorder that occurs in 10% to 15% of people who smoke, an estimated 16 million Americans. Asthma is also common. Spirometry is generally used to detect early COPD in smokers and to evaluate patients with respiratory symptoms. Although COPD and asthma account for most obstructive lung diseases, a broad spectrum of other disorders, including bronchiectasis, upper airway lesions, bronchiolar diseases, and some interstitial lung diseases, are associated with airflow obstruction. These less common forms of obstructive lung diseases are often misdiagnosed because of their uncommon occurrence and poor recognition. We describe the heterogeneous spectrum of disorders that can present with evidence of airflow obstruction and outline a diagnostic approach to obstructive lung disease.     

Differential diagnosis of adult asthma

Although the term "all that wheezes is not asthma" is not new, and the long list of asthma masqueraders has remained essentially the same for several decades, the importance of knowing when to question the accuracy ofa diagnosis of asthma has remained critical for physicians who care for patients with respiratory symptoms. The concepts of "asthma control" and"asthma severity" are currently evolving, although the fundamental hall-marks that define the syndrome of asthma endure and should be mastered by asthma specialists. Asthma masqueraders, including several that may confound a correct diagnosis of asthma, are important to consider when either the presentation of asthma is atypical or the response of the patient to treatment is suboptimal. COPD and VCD head the list of diagnoses most likely to be confused with asthma in everyday practice. Correctly identifying the diagnosis of COPD enables implementation of an up-to-date treatment plan that differs from asthma management. VCD is a vastly under recognized syndrome whose existence is widely accepted but whose pathophysiology is poorly understood, and correctly identifying a VCD component to asthma symptoms enables both a reduction in costly and potentially harmful asthma medications and focus on specific VCD treatment, such as speech therapy. For less common and uncommon asthma masqueraders, it is important to be familiar with their typical clinical presentation and basic diagnostic approaches.     

慢性阻塞性肺疾病患者一种新的炎症标志物——脂连素

目的 测定慢性阻塞性肺疾病急性加重期(AECOPD)和COPD稳定期患者血清、诱导痰中脂连素(Adiponectin,APN)水平,以探讨APN在COPD发病机制中的作用.方法 采用前瞻性观察研究,收集2008年10月至2009年10月上海市第五人民医院急诊科30例男性AECOPD患者(A组)、呼吸科门诊30例男性COPD稳定期患者(B)组及30例男性非吸烟健康体检者(C组)的血清和诱导痰.所有入选对象均为正常体质量的男性(BMI范围为18.5～24.9 kg/m2),并排除严重支气管哮喘、支气管扩张及自身免疫系统等疾病.计数诱导痰中细胞总数并分类,采用ELISA法测定血清和诱导痰中APN与白介素-8(IL-8)、白介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)的水平,并测定三组人群的肺功能.组间资料比较用成组t检验、方差分析或非参数检验,相关性分析用Pearson相关或Spearmn秩相关.结果 A组血清、诱导痰中APN水平显著高于B组和C组(P＜0.01),B组血清、诱导痰中APN水平显著高于C组(P＜0.01).A组血清、诱导痰中APN与IL-8,TNF-α呈正相关(r值分别0.739,0.734,0.852,0.857,P＜0.05).B组血清、诱导痰中APN与IL-8,TNF-2呈正相关(r值分别为0.751,0.659,0.707,0.867,P＜0.05).A组诱导痰中APN与气道中性粒细胞呈正相关(r=0.439,P＜0.05).结论 APN参与了COPD的全身和气道炎症过程,此过程与气道中性粒细胞和IL-8,TNF-α等炎症因子有关,可作为一种新的炎症标志物.     

New insights into the relationship between airway inflammation and asthma

Asthma is a condition characterized by variable airflow obstruction, airway hyper-responsiveness (AHR) and airway inflammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the specific immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inflammation. However, the relationship between inflammation and asthma is complex, with no good correlation between the severity of inflammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inflammatory response, but no asthma, as measured by variable airflow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inflammation, and neutrophilic inflammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only difference we observed was that, in asthma, the airway smooth muscle (ASM) was infiltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inflammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inflammation. Thus, if inflammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved -- for reasons that remain to be established -- that asthma occurs.     

Pathogenesis of asthma

There is now strong evidence that airway inflammation is a predominant underlying problem in patients with asthma, and it has been suggested that ongoing inflammation may lead to airway injury and remodeling. There is also recent evidence that longstanding asthma could be associated with loss of elastic recoil, which can enhance airway obstruction and worsen asthma control [82,83]. Therefore, the use of anti-inflammatory therapy has been advocated in all guidelines, including the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report [84] and its recent update [85] that recommended inhaled steroids as a first mode of therapy for patients with mild, moderate, or severe, persistent asthma. There is preliminary evidence that early institution of anti-inflammatory therapy might lead to disease modification and limit the progression of subepithelial fibrosis and airway remodeling. The pathogenesis of asthma clearly involves many cells and mediators, although the contribution of each individual factor is probably different from patient to patient depending on the setting and stimulus. Although currently available therapies are highly effective in controlling asthma symptoms and limiting exacerbations in the majority of patients, there is still a subset of patients that proceed to develop severe asthma with decreased lung function, lack of responsiveness to therapy, or frequent exacerbations. It is hoped that rapid progress in the area of asthma genetics and pharmacogenetics will yield a more precise and patient-specific understanding of asthma pathogenesis and allow practitioners to prescribe therapies that are designed for a particular patient or exacerbation. That will undoubtedly help to improve the care of asthma, limit its morbidity, and reduce the side effect of medications.     

白细胞介素4、白细胞介素8、白细胞介素10在哮喘和慢性阻塞性肺疾病发病中的作用

目的:探讨外周血白细胞介素4(IL-4)、白细胞介素8(IL-8)、白细胞介素10(IL-10)在哮喘和慢性阻塞性肺疾病(COPD)发病中的作用。方法:采用双抗体夹心酶联免疫吸附法(ELISA)分别检测急性发作期和缓解期哮喘患者各50例(哮喘组)、急性加期和缓解期COPD患者各50例(COPD组)及健康志愿者50例(健康对照组)血清中IL-4、IL-8、IL-10的水平。结果:哮喘组急性发作期IL-4、IL-8水平均显著高于缓解期(P<0.01),且2期均显著高于正常对照组(P<0.01);哮喘组急性发作期IL-10水平显著低于缓解期(P<0.01),且2期均显著低于健康对照组(P<0.01)。COPD组急性加重期IL-4、IL-8水平均显著高于缓解期(P<0.01),且2期均显著高于健康对照组(P<0.01)。哮喘组急性发作期IL-10水平显著低于缓解期(P<0.01),且2期均显著低于健康对照组(P<0.01)。哮喘急性加重期IL-4水平显著高于COPD急性加重期(P<0.01);COPD急性加重期IL-8水平高于哮喘急性发作期(P<0.01);哮喘急性发作期IL-10水平显著低于COPD急性发作期(P<0.01)。结论:IL-4、IL-8、IL-10均参与了哮喘和COPD的气道炎性反应,IL-4、IL-8是促炎因子,而IL-10是抑炎因子。IL-4在哮喘的气道炎症形成中起重要的作用。而IL-8、IL-10为COPD的主要炎症因子。     

Treatment of severe asthma: entering the era of targeted therapy

Introduction: It is estimated that 5 – 10% of asthma patients suffer from severe asthma. Severe asthma is associated with increased morbidity and mortality. These patients are not controlled with currently available treatments and therefore additional treatment options are needed. Asthma is a heterogeneous disease, and different asthma patient groups probably have different underlying pathophysiology. Novel therapies with, for example, monoclonal antibodies that target certain immunological pathways have become available. These novel treatments are not effective in all patients but only in certain phenotypes.

Areas covered: This review covers the current evidence and novel developments in treatment with monoclonal antibodies in different asthma phenotypes. This includes monoclonal antibodies against IgE, against interleukin (IL)-5 and antibodies targeting IL-13 pathways. Although there is a certain overlap between patient groups benefiting from these treatments, a more detailed identification of responder profiles for these therapies is needed for personalized therapy.

Expert opinion: In recent years, novel monoclonal antibodies have been developed, which are a promising addition to existing therapy in the treatment of severe asthma with eosinophilic inflammation and Th2-driven disease. We expect that several of the new antibodies will become available for clinical practice. In addition, it must be acknowledged that so far no effective strategies are available for patients with non-eosinophilic asthma and further research and development is necessary for this patient group.