Prospects for new drugs for chronic obstructive pulmonary disease

No currently available treatments have been shown to slow the progression of chronic obstructive pulmonary disease (COPD) or suppress the inflammation in small airways and lung parenchyma. However, several new treatments are in clinical development; some target the inflammatory process and others are directed against structural cells. A group of specific therapies are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD; these include agents directed against adhesion molecules and chemokines, as well as therapies to oppose tumour necrosis factor alpha and increase interleukin 10. Broad-range anti-inflammatory drugs are now in phase III development for COPD; they include inhibitors of phosphodiesterase 4. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor kappaB, and phosphoinositide-3-kinase gamma. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase, and antagonists of leukotriene B4 receptor. Inhibitors of epidermal-growth-factor-receptor kinase and calcium-activated chloride channels have the potential to prevent overproduction of mucus. Therapy to inhibit fibrosis is being developed against transforming growth factor beta1 and protease-activated receptor 2. There is also a search for inhibitors of serine proteinases and matrix metalloproteinases to prevent lung destruction and the development of emphysema, as well as drugs such as retinoids that might even reverse this process. Effective delivery of drugs to the sites of disease in the peripheral lung is an important consideration, and there is a need for validated biomarkers and monitoring techniques in early clinical studies with new therapies for COPD.     

Pathology and pathophysiology of chronic obstructive pulmonary disease

A variety of pathological changes have been observed in the central airways, peripheral airways and lung parenchyma of patients with chronic obstructive pulmonary disease (COPD). The characteristic changes in the central airways include inflammatory cellular infiltration into the airway wall and mucous gland enlargement. In the peripheral airways, various morphological changes are observed, including mucous plugging, epithelial abnormalities, inflammatory cellular infiltrates, fibrosis and distortion; these changes lead to airway narrowing. In the lung parenchyma, emphysema defined as alveolar destruction and airspace enlargement is present. Although the major sites of airflow limitation in patients with COPD are most likely the peripheral airways, lesions in both the peripheral airways and the lung parenchyma contribute to chronic airflow limitations.     

化学趋化因子在慢性阻塞性肺疾病中的作用

慢性阻塞性肺疾病(chronic obstructive pulmonary diseases,COPD)是一组以气流受限,且不完全可逆为特征的肺部疾病,认为与肺部对有害气体或有毒颗粒的异常炎症反应有关.目前仍缺乏有效的治疗手段.其诱发慢性炎症的具体细胞分子学机制仍不清楚.然而,越来越多的证据表明香烟诱导的炎症细胞的募集取决于趋化因子及其配体的调节.这里主要探讨CXC-和CC-家族与各种炎性细胞的相互调节,通过阻断趋化因子而减少COPD患者的炎性细胞浸润及实质破坏可能为一种有效的抗炎策略.     

CD8+ve cells in the lungs of smokers with chronic obstructive pulmonary disease.

Previous studies have shown an increased number of inflammatory cells and, in particular, CD8+ve cells in the airways of smokers with chronic obstructive pulmonary disease (COPD). In this study we investigated whether a similar inflammatory process is also present in the lungs, and particularly in lung parenchyma and pulmonary arteries. We examined surgical specimens from three groups of subjects undergoing lung resection for localized pulmonary lesions: nonsmokers (n = 8), asymptomatic smokers with normal lung function (n = 6), and smokers with COPD (n = 10). Alveolar walls and pulmonary arteries were examined with immunohistochemical methods to identify neutrophils, eosinophils, mast cells, macrophages, and CD4+ve and CD8+ve cells. Smokers with COPD had an increased number of CD8+ve cells in both lung parenchyma (p < 0.05) and pulmonary arteries (p < 0.001) as compared with nonsmokers. CD8+ve cells were also increased in pulmonary arteries of smokers with COPD as compared with smokers with normal lung function (p < 0.01). Other inflammatory cells were no different among the three groups. The number of CD8+ve cells in both lung parenchyma and pulmonary arteries was significantly correlated with the degree of airflow limitation in smokers. These results show that an inflammatory process similar to that present in the conducting airways is also present in lung parenchyma and pulmonary arteries of smokers with COPD.     

The role of airway secretions in COPD: pathophysiology, epidemiology and pharmacotherapeutic options

Often considered an aggravating but otherwise benign component of chronic obstructive pulmonary disease (COPD), airway mucus hypersecretion is now recognised as a potential risk factor for an accelerated loss of lung function in COPD and is a key pathophysiological feature in many patients, particularly those prone to respiratory tract infection. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapy including anticholinergics, beta2-adrenoceoptor agonists, alone or in combination with corticosteroids, mucolytics and macrolide antibiotics are not entirely or consistently effective in inhibiting airway mucus hypersecretion in COPD. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g., BK(Ca) channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g., benzafibrate), inhibitors of mucin exocytosis (e.g., anti-MARCKS peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g., EGF receptor tyrosine kinase inhibitors, p38 MAP kinase inhibitors, MEK/ERK inhibitors, hCACL2 blockers and retinoic acid receptor-alpha antagonists), inducers of goblet cell apoptosis (e.g., Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in COPD from that in other hypersecretory diseases of the airways. More information is required on these differences to identify therapeutic targets pertinent to COPD which, in turn, should lead to rational design of anti-hypersecretory drugs for specific treatment of airway mucus hypersecretion in COPD.     

Nonantimicrobial aspects of therapy

Current therapy for chronic obstructive pulmonary disease is symptomatic, and no treatments prevent the progression of the disease. Stopping smoking is the only effective approach, and this may be facilitated by nicotine replacement and bupropion. Treatment with short- and long-acting inhaled beta2-agonists and anticholinergics are the mainstay of therapy. Inhaled corticosteroids have no impact on disease progression, and the small reduction in exacerbations may not justify the potential systemic side effects. Supplementary oxygen therapy is indicated for acute exacerbations and chronic hypoxia. Other treatments, including mucolytics, vaccines, and respiratory stimulants are of little value. Nonpharmacological measures that are useful include pulmonary rehabilitation, exercise, good nutrition, and, in selected cases, surgery. Several new classes of drug are now in development, including mediator antagonists (leukotriene B4, interleukin-8 antagonists, and anti-oxidants) and nonsteroid anti-inflammatory drugs, of which phosphodiesterase-4 inhibitors look the most promising. There is a pressing need for a better understanding of the underlying disease process to develop more logical therapies.     

Tabakrauchen und Lungenerkrankungen

Chronic cigarette smoking is the leading cause of preventable death and primarily affects the airways and lung parenchyma. It is a well-established prime risk factor for the development of chronic obstructive pulmonary disease (COPD) and lung cancer. Chronic cigarette smoking exacerbates pre-existing diseases of the airways and the lung parenchyma such as asthma and various forms of interstitial lung diseases. Additional exposure, e.g. in an occupational setting to asbestos fibres or silica, may act synergistically to increase the risk of lung cancer and pulmonary fibrosis and also of COPD. This paper gives a synopsis of smoking-induced pulmonary diseases with respect to epidemiology and pathology and how cigarette smoking affects the prognosis.     

Chronic obstructive pulmonary disease: histopathology, inflammation and potential therapies

Chronic obstructive pulmonary disease (COPD) is a major worldwide health burden with increasing morbidity, mortality and health care cost. It is a slowly progressive chronic inflammatory condition that affects the conducting airways (both large and small) and lung parenchyma. In COPD, inflammation is evident early on even in mild disease and increases with disease severity. Recent advances in our knowledge demonstrate, by comparison with asthma, the distinctive, "abnormal" or exaggerated inflammatory processes involved in the pathogenesis of COPD and thus identify novel therapeutic targets that could potentially impact on disease progression. The present review will focus on what is known of the abnormal inflammatory response of COPD in different regions of the conducting airways and lung. Novel, potentially promising approaches to therapy are presented.     

Treating COPD with PDE 4 inhibitors

While the pathogenesis of chronic obstructive pulmonary disease (COPD) is incompletely understood, chronic inflammation is a major factor. In fact, the inflammatory response is abnormal, with CD8⁺ T-cells, CD68⁺ macrophages, and neutrophils predominating in the conducting airways, lung parenchyma, and pulmonary vasculature. Elevated levels of the second messenger cAMP can inhibit some inflammatory processes. Theophylline has long been used in treating asthma; it causes bronchodilation by inhibiting cyclic nucleotide phosphodiesterase (PDE), which inactivates cAMP. By inhibiting PDE, theophylline increases cAMP, inhibiting inflammation and relaxing airway smooth muscle. Rather than one PDE, there are now known to be more than 50, with differing activities, substrate preferences, and tissue distributions. Thus, the possibility exists of selectively inhibiting only the enzyme(s) in the tissue(s) of interest. PDE 4 is the primary cAMP-hydrolyzing enzyme in inflammatory and immune cells (macrophages, eosinophils, neutrophils). Inhibiting PDE 4 in these cells leads to increased cAMP levels, down-regulating the inflammatory response. Because PDE 4 is also expressed in airway smooth muscle and, in vitro, PDE 4 inhibitors relax lung smooth muscle, selective PDE 4 inhibitors are being developed for treating COPD. Clinical studies have been conducted with PDE 4 inhibitors; this review concerns those reported to date.     

Selective phosphodiesterase-4 inhibitors in chronic obstructive lung disease

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is usually progressive. In addition, an abnormal inflammatory response of the lungs to noxious particles or gases can be seen throughout the airways, parenchyma, and pulmonary vasculature. So far, anti-inflammatory medications (eg, inhaled corticosteroids) have failed to show a major effect on the decline of lung function in COPD patients. Novel anti-inflammatory therapies such as selective phosphodiesterase 4 (PDE4) inhibitors are in clinical development. Their potential role in the management of COPD is described in this review. RECENT FINDINGS: Some of the selective PDE4 inhibitors have demonstrated in vitro and in vivo anti-inflammatory activity on cells commonly linked to airway inflammation in COPD, such as neutrophils. While these agents seem to offer only a modest improvement in lung function compared with other bronchodilators, their anti-inflammatory effects appear to provide some substantial benefits in reducing exacerbations and improving health-related quality of life. SUMMARY: Based on the available data, the second generation of selective PDE4 inhibitors will likely provide additional therapeutic options for the management of COPD. These agents may become an important tool in the treatment of this disease, since they target three important components of COPD: airway obstruction, inflammation, and structural changes.     

Recent advances in the assessment and management of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by an abnormal inflammatory reaction of the airways and lung parenchyma. It stems from chronic tobacco smoking, and indoor air pollution, and bronchospasm is the predominant cause of the symptoms. The condition is the result of environmental insult and host reaction that is likely to be genetically predetermined. Chronic obstructive pulmonary disease exhibits expiratory airflow limitation due to abnormalities in the airways and/or lung parenchyma. The disease begins with an asymptomatic phase and onset of the symptomatic phase develops with a fall in forced expiratory volume in one second (FEV1) below 70% of the predicted value. There is reduction in diffusing capacity, hypoxaemia and alveolar hypoventilation. However, it is intriguing why only a fraction of smokers develop clinically relevant COPD.     

Pathophysiology of the small airways in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by a persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. From a pathological point of view, COPD is characterized by two distinct and frequently coexisting aspects: small airway abnormalities and parenchymal destruction (or emphysema). When pathological changes are localized in lung parenchyma, they will contribute to airflow limitation by reducing the elastic recoil of the lung through parenchymal destruction, as well as by reducing the elastic load applied to the airways through destruction of alveolar attachments. Conversely, when pathological changes involve the small airways, they will contribute to airflow limitation by narrowing and obliterating the lumen and by actively constricting the airways, therefore increasing the resistance. In this article we will review the structural abnormalities in small airways and their relationship with the disordered pulmonary function in COPD, in the attempt to disentangle the mechanisms contributing to the development and progression of airflow limitation in smokers. We will start by describing the normal structure of the small airways, and then observe the main pathological alterations that accumulate in this site and how they parallel pulmonary function derangement.     

氧化应激在慢性阻塞性肺疾病发生中的作用及防治策略

COPD 特征是慢性气道炎症、细小支气管重塑及肺实质破坏。研究表明,香烟烟雾等有害气体所引起的氧化应激在 COPD 发展过程起到了至关重要的作用。吸烟增强氧化应激,使氧化/抗氧化比例失衡,直接损伤肺组织,加重气道炎症反应,引起自身免疫反应,最终导致气流受限。因此,对抗氧化应激、提高宿主抗氧化能力,是 COPD 防治的最新着重点。     

Pulmonary biomarkers in chronic obstructive pulmonary disease

There has been increasing interest in using pulmonary biomarkers to understand and monitor the inflammation in the respiratory tract of patients with chronic obstructive pulmonary disease (COPD). In this Pulmonary Perspective we discuss the merits of the various approaches by reviewing the current literature on pulmonary biomarkers in COPD and underscore the need for more systematic studies in the future. Bronchial biopsies and bronchoalveolar lavage provide valuable information about inflammatory cells and mediators, but are invasive, so that repeated measurements have to be very limited in assessing any interventions. Induced sputum has provided considerable information about the inflammatory process, including mediators and proteinases in COPD, but selectively samples proximal airways and may not closely reflect distal inflammatory processes. Exhaled gases and breath condensate are noninvasive procedures, so repeated measurements are possible, but for some assays the variability is relatively high. There is relatively little information about how any of these biomarkers relate to other clinical outcomes, such as progression of the disease, severity of disease, clinical subtypes, or response to therapy. More information is also needed about the variability in these measurements. In the future, pulmonary biomarkers may be useful in predicting disease progression, indicating disease instability, and in predicting response to current therapies and novel therapies, many of which are now in development.     

Future directions in the pharmacologic therapy of chronic obstructive pulmonary disease

Current therapy for chronic obstructive pulmonary disease (COPD) fails to alter its relentless progression. This remains a significant challenge and unmet need. A recent advance is the demonstration that treatment with a fixed dose of an inhaled corticosteroid and a long-acting beta2-agonist in COPD improves lung function and quality of life, and reduces exacerbation more effectively than either drug alone. Other improvements include the introduction of tiotropium, a once-daily anticholinergic. In advanced clinical development are other once-daily bronchodilators and combinations of anticholinergic drugs and beta2-agonists. Increased understanding of the pathogenesis of COPD has led to novel drugs aimed at inhibiting targets, including phosphodiesterase 4, proteases, and various inflammatory mediators. Furthermore, COPD is increasingly seen as a systemic disorder or, indeed, may be a pulmonary manifestation of a complex pathophysiologic response to chronic inhalation of toxic irritants and associated with aging. Future therapy may involve better understanding of how best to target existing drugs used to treat cardiovascular disorders associated with smoking, such as atherosclerosis and hypercoagulability, and the development of new drugs that target systemic and metabolic manifestations that either result from or coexist with chronic lung inflammation, hypoxia, and cardiovascular disease in COPD.     

Pulmonary vasculature in COPD: The silent component

Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that results from an inflammatory process affecting the airways and lung parenchyma. Despite major abnormalities taking place in bronchial and alveolar structures, changes in pulmonary vessels also represent an important component of the disease. Alterations in vessel structure are highly prevalent and abnormalities in their function impair gas exchange and may result in pulmonary hypertension (PH), an important complication of the disease associated with reduced survival and worse clinical course. The prevalence of PH is high in COPD, particularly in advanced stages, although it remains of mild to moderate severity in the majority of cases. Endothelial dysfunction, with imbalance between vasodilator/vasoconstrictive mediators, is a key determinant of changes taking place in pulmonary vasculature in COPD. Cigarette smoke products may perturb endothelial cells and play a critical role in initiating vascular changes. The concurrence of inflammation, hypoxia and emphysema further contributes to vascular damage and to the development of PH. The use of drugs that target endothelium‐dependent signalling pathways, currently employed in pulmonary arterial hypertension, is discouraged in COPD due to the lack of efficacy observed in randomized clinical trials and because there is compelling evidence indicating that these drugs may worsen pulmonary gas exchange. The subgroup of patients with severe PH should be ideally managed in centres with expertise in both PH and chronic lung diseases because alterations of pulmonary vasculature might resemble those observed in pulmonary arterial hypertension. Because this condition entails poor prognosis, it warrants specialist treatment.     

慢性阻塞性肺疾病评估相关生物标志物研究进展

气流受限是COPD的主要疾病特征,其主要发生机制与吸入有毒气体或颗粒(通常是烟雾)引起的复杂的病理改变有关,包括大、小气道的炎症和肺实质破坏.慢性阻塞性肺疾病急性加重期(acute exacerbation chronic obstructive pulmonary disease,AECOPD)是造成老年人死亡的重要原因之一,早诊断、早治疗是及早阻止疾病发展、改善预后的关键.生物标志物在协助该病的病因、评估、预后及治疗方面起重要作用.评估COPD严重程度在临床工作中显得十分重要,本文综述了与COPD严重程度相关生物标志物的研究现状.     

Future treatment to lessen exacerbations of chronic obstructive pulmonary disease

Therapies currently used to reduce exacerbations of chronic obstructive pulmonary disease (COPD) are compounds used almost entirely for asthma therapy. A notable exception is tiotropium, a long-acting parasympatholytic agent. This compound and its precursor, iprotropium, are only occasionally used for asthma therapy. Likewise, leukotriene-modifying drugs are used occasionally for the treatment of COPD. In neither circumstance is there agency-approved indication for these particular cross-over therapies, but the use of long-acting beta(2)-adrenergic compounds and high-solubility inhaled steroids is a mainstay for therapy in both asthma and COPD. Similarly, theophylline, although less often used for either process, is therapeutically applicable to both asthma and COPD. Although overlap syndromes point to the occurrence of a common pathway in some cases, the inflammatory process for asthma and chronic obstructive pulmonary disease (COPD) differs substantially in most cases. Hence, the application of therapies designed to relax airway smooth muscle and ameliorate asthmatic inflammation lacks a therapeutic rationale for a disease characterized by predominant neutrophilic inflammation occurring in the small airways and alveoli. By definition, COPD is poorly reversible airflow obstruction; hence, the use of drugs designed to relax airway smooth muscle is somewhat counterintuitive and does not address the pathophysiological process of the disease.     

Hyperinflation and its management in COPD

Chronic obstructive pulmonary disease (COPD) is characterized by poorly reversible airflow limitation. The pathological hallmarks of COPD are inflammation of the peripheral airways and destruction of lung parenchyma or emphysema. The functional consequences of these abnormalities are expiratory airflow limitation and dynamic hyperinflation, which then increase the elastic load of the respiratory system and decrease the performance of the respiratory muscles. These pathophysiologic features contribute significantly to the development of dyspnea, exercise intolerance and ventilatory failure. Several treatments may palliate flow limitation, including interventions that modify the respiratory pattern (deeper, slower) such as pursed lip breathing, exercise training, oxygen, and some drugs. Other therapies are aimed at its amelioration, such as bronchodilators, lung volume reduction surgery or breathing mixtures of helium and oxygen. Finally some interventions, such as inspiratory pressure support, alleviate the threshold load associated to flow limitation. The degree of flow limitation can be assessed by certain spirometry indexes, such as vital capacity and inspiratory capacity, or by other more complexes indexes such as residual volume/total lung capacity or functional residual capacity/total lung capacity. Two of the best methods to measure flow limitation are to superimpose a flow–volume loop of a tidal breath within a maximum flow–volume curve, or to use negative expiratory pressure technique. Likely this method is more accurate and can be used during spontaneous breathing. A definitive definition of dynamic hyperinflation is lacking in the literature, but serial measurements of inspiratory capacity during exercise will document the trend of end-expiratory lung volume and allow establishing relationships with other measurements such as dyspnea, respiratory pattern, exercise tolerance, and gas exchange.     

Phosphodiesterase 4-selective inhibition: novel therapy for the inflammation of COPD

Chronic obstructive pulmonary disease (COPD), which is increasing in prevalence and a leading cause of death worldwide, is characterised by an 'abnormal' inflammatory response. There is a predominance of CD8(+) T cells, CD68(+) macrophages and, in exacerbations-neutrophils, in both conducting airways and lung parenchyma. Smoking is the most common etiological factor leading to COPD and smoking cessation is the most effective approach to the management of COPD, but it does not resolve the underlying inflammation of COPD, which persists, even in ex-smokers. The presence of mucosal inflammation serves as the rationale for anti-inflammatory therapy. However, while there are reductions in the numbers of mast cells following treatment with inhaled steroids, CD8(+), CD68(+) cells and neutrophils are refractory to such treatment, highlighting a need for additional, more targeted interventions. Phosphodiesterase 4 (PDE4) inhibitors are a promising and novel drug class that have potent activity against several key components of the inflammatory process in COPD. A recently published study has shown that the selective PDE4 inhibitor, cilomilast, reduces the numbers of bronchial mucosal CD8(+) and CD68(+) cells and neutrophils. This review focuses on the nature of the inflammation in COPD and considers how selective PDE4 inhibitors may optimize and advance our treatment of this chronic condition.