慢性阻塞性肺病和骨质疏松

慢性阻塞性肺病(COPD)不仅是肺部疾病,而且是一种全身性疾病.骨质疏松是COPD患者的肺外表现之一.随着COPD患者病情加重,骨质疏松的发病率亦有所增加.但COPD患者发生骨质疏松的机制至今尚未完全明确.探讨COPD患者骨质疏松症的发生情况及影响因素,有助于提高对COPD发生骨质疏松的早期认识,预防骨质疏松的发生、发展,对改进COPD患者的生活质量和延长生命具有重要意义.     

吸烟对慢性阻塞性肺疾病气道基因表达影响研究新进展

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)是一种具有气流受限特征的可以预防和治疗的疾病,气流受限不完全可逆、呈进行性发展,与肺部对香烟烟雾等有害气体或有害颗粒的异常炎症反应有关。COPD患病率及致残率高,吸烟为目前公认的危险因素,然而仅一部分吸烟者才发展成为...     

Modifying the Course of Chronic Obstructive Pulmonary Disease: Looking Beyond the FEV1

Abstract

COPD is defined by airflow limitation that is not fully reversible and is usually progressive. Thus, airflow obstruction (measured as FEV₁) has traditionally been used as the benchmark defining disease modification with therapy. However, COPD exacerbations and extrapulmonary effects are common and burdensome and generally become more prominent as the disease progresses. Therefore, disease progression should be broader than FEV₁ alone. Interventions that reduce the frequency or severity of exacerbations or ameliorate extrapulmonary effects should also be considered disease modifiers. A narrow focus on FEV₁ will fail to capture all the beneficial effects of therapy on disease modification. Although smoking cessation has been unequivocally demonstrated to slow the rate of FEV₁ decline, inhaled corticosteroid–long-acting bronchodilator therapy may also have modest effects according to post hoc analysis. Maintenance pharmacotherapy with inhaled long-acting anti-muscarinic or ®-adrenergic agents or combined ®-adrenergic—inhaled corticosteroid reduces symptoms, improves lung function, reduces the frequency of exacerbations, and improves exercise capacity and HRQL. Pulmonary rehabilitation reduces symptom burden, increases exercise capacity, improves HRQL, and reduces health care utilization, probably through reducing the severity of exacerbations. Smoking cessation, lung volume reduction surgery, inhaled maintenance pharmacotherapy, and pulmonary rehabilitation administered in the post-exacerbation period may reduce mortality in COPD. These improvements over multiple outcome areas and over relatively long durations suggest that disease modification is indeed possible with existing therapies for COPD. Therefore, therapeutic nihilism in COPD is no longer warranted.     

炎性因子在慢性阻塞性肺疾病气道炎症中的作用

COPD是一种以气道慢性炎症为特征之一的慢性呼吸系统疾病,气道炎性反应在COPD占有重要作用。炎性细胞因子是机体内最重要的一类细胞因子,多种炎性细胞因子参与气道炎症的病理生理机制,对肺组织和支气管产生损害,并发肺外效应。在COPD的自然病程中存在炎性细胞因子网络系统,调控COPD的气道炎症的发生发展。     

Telomere shortening in chronic obstructive pulmonary disease

Chronic oxidative stress and systemic inflammation contribute to the pathology of several chronic diseases, one among which is chronic obstructive pulmonary disease (COPD). In addition, increased oxidative stress and inflammation have been observed to be negatively associated with telomere length (TL). Our aim was to investigate the TL in COPD patients in relation to pulmonary and extrapulmonary disease severity. Furthermore, based on experimental evidence suggesting the effects of oxidative stress on telomere shortening, we studied the association of TL with the antioxidant enzyme superoxide dismutase (SOD). One hundred and two COPD patients with moderate to severe COPD were studied and compared with 19 healthy age-matched controls. Patients were characterized by elevated levels of inflammatory markers (CRP, sTNF-receptors) and lower SOD-activity than the controls (p<0.001), irrespective of the SOD genotype. TL was negatively associated with age (p<0.01) and was significantly shorter in COPD patients than controls (p<0.05). Within the patient group age-adjusted TL variability could not be explained by lung function and smoking history but a modest association was found with the percentage of fat mass (p<0.05). These data provide evidence for a relationship between a disturbed oxidant/antioxidant balance and telomere shortening and indicate that preservation of fat mass may be protective in delaying telomere shortening in COPD patients.     

慢性阻塞性肺疾病的全身性炎症影响

目前研究显示慢性阻塞性肺疾病（COPD）并不仅是肺部疾病，而且是一种全身性疾病。它的病理生理改变主要是由于肺部炎症引起全身性炎症，继而引起COPD患者的肺外表现，包括营养不良、体重下降、骨骼肌损耗、骨质疏松以及对心血管、神经系统等全身影响。认识COPD全身性炎症的改变，可能对临床评估患者病情和治疗产生深远的影响。     

The preclinical pharmacology of roflumilast – A selective,oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease

After more than two decades of research into phosphodiesterase 4 (PDE4) inhibitors, roflumilast (3-cyclopropylmethoxy-4-difluoromethoxy-N-[3,5-di-chloropyrid-4-yl]-benzamide) may become the first agent in this class to be approved for patient treatment worldwide. Within the PDE family of 11 known isoenzymes, roflumilast is selective for PDE4, showing balanced selectivity for subtypes A–D, and is of high subnanomolar potency. The active principle of roflumilast in man is its dichloropyridyl N-oxide metabolite, which has similar potency as a PDE4 inhibitor as the parent compound. The long half-life and high potency of this metabolite allows for once-daily, oral administration of a single, 500-μg tablet of roflumilast.The molecular mode of action of roflumilast – PDE4 inhibition and subsequent enhancement of cAMP levels – is well established. To further understand its functional mode of action in chronic obstructive pulmonary disease (COPD), for which roflumilast is being developed, a series of in vitro and in vivo preclinical studies has been performed.COPD is a progressive, devastating condition of the lung associated with an abnormal inflammatory response to noxious particles and gases, particularly tobacco smoke. In addition, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), significant extrapulmonary effects, including comorbidities, may add to the severity of the disease in individual patients, and which may be addressed preferentially by orally administered remedies. COPD shows an increasing prevalence and mortality, and its treatment remains a high, unmet medical need.In vivo, roflumilast mitigates key COPD-related disease mechanisms such as tobacco smoke-induced lung inflammation, mucociliary malfunction, lung fibrotic and emphysematous remodelling, oxidative stress, pulmonary vascular remodelling and pulmonary hypertension. In vitro, roflumilast N-oxide has been demonstrated to affect the functions of many cell types, including neutrophils, monocytes/macrophages, CD4+ and CD8+ T-cells, endothelial cells, epithelial cells, smooth muscle cells and fibroblasts. These cellular effects are thought to be responsible for the beneficial effects of roflumilast on the disease mechanisms of COPD, which translate into reduced exacerbations and improved lung function. As a multicomponent disease, COPD requires a broad therapeutic approach that might be achieved by PDE4 inhibition. However, as a PDE4 inhibitor, roflumilast is not a direct bronchodilator.In summary, roflumilast may be the first-in-class PDE4 inhibitor for COPD therapy. In addition to being a non-steroid, anti-inflammatory drug designed to target pulmonary inflammation, the preclinical pharmacology described in this review points to a broad functional mode of action of roflumilast that putatively addresses additional COPD mechanisms. This enables roflumilast to offer effective, oral maintenance treatment for COPD, with an acceptable tolerability profile and the potential to favourably affect the extrapulmonary effects of the disease.     

COPD: a multifactorial systemic disease

Chronic obstructive pulmonary disease (COPD) has traditionally been considered a disease of the lungs secondary to cigarette smoking and characterized by airflow obstruction due to abnormalities of both airway (bronchitis) and lung parenchyma (emphysema). It is now well known that COPD is associated with significant systemic abnormalities, such as renal and hormonal abnormalities, malnutrition, muscle wasting, osteoporosis, and anemia. However, it is still unclear whether they represent consequences of the pulmonary disorder, or whether COPD should be considered as a systemic disease. These systemic abnormalities have been attributed to an increased level of systemic inflammation. Chronic inflammation, however, may not be the only cause of the systemic effects of COPD. Recent data from humans and animal models support the view that emphysema may be a vascular disease. Other studies have highlighted the role of repair failure, bone marrow abnormality, genetic and epigenetic factors, immunological disorders and infections as potential causes of COPD systemic manifestations. Based on this new evidence, it is reasonable to consider COPD, and emphysema in particular, as 'a disease with a significant systemic component' if not a 'systemic disease' per se. The aim of this review is to give an overview of the most relevant and innovative hypothesis about the extrapulmonary manifestations of COPD.     

Phenotypes of chronic obstructive pulmonary disease

The current clinical classification of smoking-related lung disease fails to take into account the heterogeneity of chronic obstructive pulmonary disease (COPD). With an increased understanding of pathophysiologic variation, COPD now clearly represents a spectrum of overlapping diseases with important extrapulmonary consequences. A "phenotype" describes the outward physical manifestations of a particular disease, and compromises anything that is part of the observable structure, function or behavior of an individual. Such phenotypic distinctions in COPD include: frequent exacerbator, pulmonary cachectic, rapid decliner, airways hyperresponsiveness, impaired exercise tolerance, and emphysema versus airways disease. These variable manifestations, each with unique prognostic, clinical and physiologic ramifications, represent distinct phenotypes within COPD. While all of these phenotypes have smoking as a common risk factor, the other risk factors that determine these phenotypes remain poorly understood. An individual smoker has variable expression of each phenotype and there is mounting evidence that COPD phenotypes have different clinical outcomes. These phenotypes can be broadly classified into one of three groups: clinical, physiologic and radiographic. This review presents the evidence for the spectrum of COPD phenotypes with a focused discussion on the pathophysiologic, epidemiologic and clinical significance of each subtype.     

Prevalence of anemia in chronic obstructive pulmonary disease: comparison to other chronic diseases

Chronic obstructive pulmonary disease (COPD) is a multisystemic inflammatory disease characterized by pulmonary and extrapulmonary symptoms. The impaired lung function has long-term implications on metabolism and homeostasis of many organ systems such as the skeleton, heart, brain and skeletal muscle. The occurrence and prevalence of anemia in COPD has rarely been studied. Anemia is such a common and simple clinical finding that we may underestimate its physiological relevance in COPD. The aim of the study was to retrospectively investigate the prevalence of anemia in a large population of COPD patients and to compare it to patients with chronic heart failure, renal insufficiency, cancer and asthma. A population of 7337 patients that was treated in the University Hospital Charité, Berlin, Germany, from 1996 to 2003 was subsetted according to the ICD-9/10 code of the discharge diagnoses into the above-mentioned diagnoses groups. The overall prevalence of anemia in COPD patients was 23.1%. It was comparable to the prevalence of anemia we found in patients with chronic heart failure (23.3%). Patients with renal insufficiency and cancer presented the highest anemia frequencies. The high prevalence of anemia in hospitalised COPD patients that were treated mostly for exacerbations gives evidence that anemia is also a comorbidity in COPD and may contribute to exercise limitation and dyspnoea.     

True Restrictive Ventilatory Pattern in Asthma

Asthma is characterized by a reversible bronchial obstruction. Some patients may present a restrictive lung function pattern. Most often, this is due to extrapulmonary causes such as obesity, scoliosis, etc. As in chronic obstructive pulmonary disease (COPD), a “pseudorestriction,” a lowered forced vital capacity (FVC) due to dynamic hyperinflation with air trapping, may be seen. This article presents two patients suffering from asthma who had an considerable impairment of total lung capacity (TLC) and FVC when their asthma was poorly controlled, showing a complete reversibility of restriction when treated properly for the asthma.     

慢性阻塞性肺疾病患者内分泌激素变化

慢性阻塞性肺疾病是一种慢性呼吸系统的常见病、多发病,它不仅累及肺,同时也可以累及全身,而全身主要表现为内分泌激素的变化,本文就慢性阻塞性肺疾病患者肺外表现与甲状激素、瘦素与胰岛素分泌之间的联系作一简要综述.     

慢性阻塞性肺疾病伴发营养不良的机制及其干预研究进展

目前研究表明,慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)除了会出现特征性的肺部病理改变外,也可以引起全身(或称肺外)的不良反应,即COPD的肺外效应(全身效应).其中营养不良是COPD常见的肺外效应,其对疾病的发展及预后有着重要影响.以下就目前国内外有关CO...     

The natural history of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the USA, and it remains one of the few diseases that continues to increase its numbers. The development and progression of COPD can vary dramatically between individuals. A low level of lung function remains the cornerstone of COPD diagnosis and is a key predictor of prognosis. Lung function, however, is not the only factor in determining morbidity and mortality related to COPD, with factors such as body mass index, exercise capability and comorbid disease being important predictors of poor outcomes. Exacerbations of COPD are additional important indicators of both quality of life and outcomes in COPD patients. Definitions of exacerbations can vary, ranging from an increase in symptoms to COPD-related hospitalisations and death. COPD exacerbations are more common in patients with lower levels of lung function and may lead to more rapid declines in lung function. Better understanding of the natural history of COPD may lead to better definitions of specific COPD phenotypes, better interventions and improved outcomes.     

Extrapulmonary effects of chronic obstructive pulmonary disease

Although airflow obstruction is the most obvious and most studied manifestation of chronic obstructive pulmonary disease (COPD), it should not be overlooked that COPD, particularly in its later stages, is associated with many extrapulmonary features that contribute to the morbidity, reduced quality of life, and, possibly, mortality of this disease. We review here the literature on skeletal muscle dysfunction, osteoporosis, and weight loss in COPD, with particular attention to possible approaches to their management. Patients with COPD may also have other extrapulmonary effects such as hormonal abnormalities that could probably be corrected, but less is known about them. COPD, therefore, should be regarded as a systemic disorder. Its systemic manifestations should not be overlooked in the overall care of the patient, because there are important ways in which they can be addressed.     

Intronic single-nucleotide polymorphisms in Bcl-2 are associated with chronic obstructive pulmonary disease severity

BACKGROUND AND OBJECTIVE: COPD is a multifactorial disease influenced by genetic and environmental factors, and gene-by-environmental interactions. There is considerable variability in the degree of airflow obstruction, moreover only 10-15% of chronic smokers develop COPD. These observations indicate that additional risk factors, possibly genetic, contribute to not only the susceptibility to COPD but also the development and severity of COPD. Recent paradigms highlight the presence and causal role of apoptosis in emphysema. There is a large amount of information on the genes involved in the regulation of apoptosis and one of the most studied is Bcl-2. The aim of this study was to investigate the genetic association of Bcl-2 gene with the level of lung function, that is, the severity, of COPD. METHODS: The genetic association of Bcl-2 polymorphisms with lung function was investigated in 261 Japanese patients with COPD using 12 single-nucleotide polymorphisms (SNPs) in Bcl-2. RESULTS: Four SNPs showed a significant association between the high and low lung function groups in a dominant trait comparison. Subsequent linkage-disequilibrium mapping and analyses of haplotype structure also showed a significant association between the level of lung function and two haplotypes comprised of the associated SNPs in Bcl-2. CONCLUSIONS: Although the linkage between Bcl-2 gene and the susceptibility to COPD remains to be clarified, the findings of the current study indicate that Bcl-2 might be influencing the level of lung function, that is, the development and severity of COPD.     

慢性阻塞性肺疾病合并症研究进展

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)表现为慢性肺部及全身炎症反应,以进行性不完全可逆性气流受限为特征.COPD患者往往合并一种或多种肺外症状(COPD合并症),这可能是COPD慢性炎症反应的伞身表现,也可能与共同的危险因素(如吸烟、年龄等)有关.这些合...     

慢性阻塞性肺疾病系统性炎症的治疗进展

慢性阻塞性肺疾病机制复杂,不仅表现为肺部的局部炎症,而且存在系统性炎症反应,后者导致一些肺外器官受损.目前,正在研究针对于控制系统性炎症的新的治疗方法.综述了治疗COPD患者系统性炎症的新方法.     

慢性阻塞性肺疾病系统性炎症的治疗进展

慢性阻塞性肺疾病机制复杂,不仅表现为肺部的局部炎症,而且存在系统性炎症反应,后者导致一些肺外器官受损.目前,正在研究针对于控制系统性炎症的新的治疗方法.综述了治疗COPD患者系统性炎症的新方法.     

Genetics of chronic obstructive pulmonary disease

Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.