COPD

Chronic obstructive lung disease (COPD) is characterized by airflow limitation that is not fully reversible and usually progressive. The disease is associated with an inflammatory response of the lungs to noxious particles, mainly cigarette smoke. Numerous studies suggest a significant association between impaired lung function and the presence of extrapulmonary comorbidities. Systemic inflammation is believed to be a link between COPD and its extrapulmonary manifestations although the exact mechanisms remain unclear. The development and validation of score systems that classify COPD severity not only by lung function represent a new understanding of the disease. This warrants novel therapeutic approaches.     

Mortality in COPD: Role of comorbidities.

Chronic obstructive pulmonary disease (COPD) represents an increasing burden throughout the world. COPD-related mortality is probably underestimated because of the difficulties associated with identifying the precise cause of death. Respiratory failure is considered the major cause of death in advanced COPD. Comorbidities such as cardiovascular disease and lung cancer are also major causes and, in mild-to-moderate COPD, are the leading causes of mortality. The links between COPD and these conditions are not fully understood. However, a link through the inflammation pathway has been suggested, as persistent low-grade pulmonary and systemic inflammation, both known risk factors for cardiovascular disease and cancer, are present in COPD independent of cigarette smoking. Lung-specific measurements, such as forced expiratory volume in one second (FEV(1)), predict mortality in COPD and in the general population. However, composite tools, such as health-status measurements (e.g. St George's Respiratory Questionnaire) and the BODE index, which incorporates Body mass index, lung function (airflow Obstruction), Dyspnoea and Exercise capacity, predict mortality better than FEV(1) alone. These multidimensional tools may be more valuable because, unlike predictive approaches based on single parameters, they can reflect the range of comorbidities and the complexity of underlying mechanisms associated with COPD. The current paper reviews the role of comorbidities in chronic obstructive pulmonary disease mortality, the putative underlying pathogenic link between chronic obstructive pulmonary disease and comorbid conditions (i.e. inflammation), and the tools used to predict chronic obstructive pulmonary disease mortality.     

Chronic bronchitis, COPD

Chronic bronchitis is part and precursor of COPD, a complex disease triggered mostly by exposure to cigarette smoke. However COPD develops only in patients with specific susceptibility probably determined by genetic factors or additional risk factors. A specific type of inflammation resides in the bronchial and bronchiolar walls, that infers damage not only to airway structure but also to surrounding alveolar attachments and thus to the lung parenchyma. Chronic bronchitis, fibrosing bronchiolitis and emphysema constitute the three main stems of pathology of the disease but may coexist with varying extent. The clinical picture is therefore quite variable. Treatment exists largely in bronchodilation combining different mechanisms and using long acting drugs usually applied by inhalation. Acute exacerbations promote progression of the disease, which must be counteracted by adaptation and intensification of therapy, in some cases including non invasive or invasive ventilation. Several non-pharmacologic measures such as smoking cessation, rehabilitation, nutritional support, long term oxygen therapy, lung volume reduction and possibly lung transplantation may be available for appropriate patients and have to be considered.     

Chronische Bronchitis, COPD

Chronic bronchitis is part and precursor of COPD, a complex disease triggered mostly by exposure to cigarette smoke. However COPD develops only in patients with specific susceptibility probably determined by genetic factors or additional risk factors. A specific type of inflammation resides in the bronchial and bronchiolar walls, that infers damage not only to airway structure but also to surrounding alveolar attachments and thus to the lung parenchyma. Chronic bronchitis, fibrosing bronchiolitis and emphysema constitute the three main stems of pathology of the disease but may coexist with varying extent. The clinical picture is therefore quite variable. Treatment exists largely in bronchodilation combining different mechanisms and using long acting drugs usually applied by inhalation. Acute exacerbations promote progression of the disease, which must be counteracted by adaptation and intensification of therapy, in some cases including non invasive or invasive ventilation. Several non-pharmacologic measures such as smoking cessation, rehabilitation, nutritional support, long term oxygen therapy, lung volume reduction and possibly lung transplantation may be available for appropriate patients and have to be considered.     

Systemic manifestations of COPD

COPD is characterized by a poorly reversible airflow limitation resulting from chronic inflammation, mainly due to tobacco exposure. Over the past few years, the understanding of COPD has evolved from it being a disease affecting the lungs to it being a complex, heterogeneous, and generalized disorder in an aging population. Extrapulmonary comorbidities significantly complicate the management and influence the prognosis of patients with COPD. Although certain comorbidities like cardiovascular diseases share some risk factors with COPD, such as cigarette smoking, other frequently observed comorbidities, including musculoskeletal wasting, metabolic syndrome, and depression, cannot be easily attributed to smoking. There is increasing evidence that chronic inflammation is a key factor in COPD and that inflammation might be the common pathway linking these comorbidities and explaining why they typically develop together. Physicians treating patients with COPD need to become aware of these extrapulmonary aspects. Any patient with COPD should be carefully evaluated for comorbidities and the systemic consequences of COPD since they not only influence the prognosis but also have an impact on disease management. The treatment of COPD is no longer focused exclusively on inhaled therapy but is taking on a multidimensional approach, especially because the treatment of the comorbidities might positively affect the course of COPD itself.     

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.     

COPD: a pediatric disease

Chronic obstructive pulmonary disease (COPD) is conventionally thought of as a disease of adult smokers, related to airway inflammation and structural airway changes (remodeling). However, there is important epidemiological evidence, from a series of studies with overlapping age groups from birth to late middle age that early life events, including antenatal influences on lung growth, program the child to be at increased risk for future COPD. This paper reviews the evidence for potential gene: environment interactions in this process, in particular with respect to the maternal genotype of the COPD patient. It explores the hypothesis that genes important in early lung development are also important in determining adult risk for COPD. Although the major preventable factor adversely impacting on child lung health is maternal smoking, the effects of viral infection, nutrition, and indoor and outdoor pollution are reviewed. The survivors of preterm birth are another important cohort who may develop premature COPD in adult life. Early life events provide the substrate for COPD, with later cigarette smoking, and occasionally other exposures, pulling the trigger to produce COPD. Although a rigorous anti-smoking program is necessary to halt this spiral of lung destruction leading to COPD, a focus on early (including prenatal) lung health is also important. Any model of COPD which does not take into account early life influences is likely to be fatally flawed.     

Smoking cessation improves both direct and indirect airway hyperresponsiveness in COPD.

Smoking induces chronic obstructive pulmonary disease (COPD) and is associated with airway inflammation and airway hyperresponsiveness (AHR). It has not been studied in COPD whether direct (methacholine) and indirect (adenosine-5'-monophosphate (AMP)) stimuli are associated with airway inflammation and neither whether smoking cessation improves these features. The current authors cross-sectionally investigated the relationship of AHR to methacholine and AMP with lung function and inflammatory cells in the sputum of 33 smokers with COPD. In addition, changes in these parameters were prospectively assessed in 14 smokers who successfully quit smoking for 1 yr. The presence of AHR to both methacholine and AMP was associated with lower lung function, but not with sputum inflammation. AHR to methacholine and AMP improved significantly after a 1-yr smoking cessation, yet this was unrelated to changes in sputum cell counts. The numbers of neutrophils and epithelial cells significantly increased with smoking cessation. Both direct and indirect airway hyperresponsiveness are associated with lower lung function, but not with sputum inflammation in chronic obstructive pulmonary disease. Interestingly, 1-yr smoking cessation improved both direct and indirect airway hyperresponsiveness, yet without a significant association with changes in lung function or sputum inflammation. Thus, other factors are likely to induce these improvements, e.g. a reduction in stimulation of irritant receptors, airway wall changes or mucus hypersecretion.     

Functional significance of apoptosis in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disease characterized by an abnormal inflammatory response of the lungs to noxious particles and gases. Cigarette smoking remains a major risk factor in COPD development. Accumulating evidence suggests that apoptosis, a regulated form of cell death, may play an important role in COPD pathogenesis. Increased numbers of apoptotic cells can be detected in lung tissue and airways of human subjects with COPD, relative to normal lungs or those from smokers without COPD. Alveolar wall destruction associated with emphysema development, may involve increased apoptosis of alveolar structural cells. Several intervention-induced apoptotic models (e.g., cigarette smoke, vascular-endothelial growth factor inhibition, and interferon-gamma) cause emphysematous changes in vitro and in vivo. Increased apoptosis in COPD can also imply defects in the normal physiological clearance of apoptotic cells. Additional factors that relate to perpetuation of the pathogenesis of COPD, including protease/antiprotease imbalance, inflammation and oxidative stress, may mutually promote apoptosis or contribute to impaired clearance of apoptotic cells. Given that cigarette smoking is the most common cause of COPD, identification of the pathways of cigarette smoke-induced apoptosis may further the understanding of COPD pathogenesis. However, apoptosis rate is not diminished after cessation of cigarette smoking, indicating that other mechanisms perpetuate apoptosis in COPD. Therefore, understanding functional relationships between apoptosis and protease/antiprotease imbalance, inflammation, oxidative stress and other factors potentially involved in COPD pathogenesis may uncover crucial therapeutic targets.     

Approaches to slowing the progression of COPD

Chronic obstructive pulmonary disease (COPD) is a major health problem across the world and its medical, societal and economic impacts continue to grow. There are several hypotheses regarding the pathogenesis of COPD and important new information on airway inflammation, oxidative stress and proteolysis in the lungs that are important for the development of effective treatments. The differences in susceptibility to COPD among cigarette smokers and the common familial risk of developing disease point to important genetic influences. The identification of candidate gene loci and various gene polymorphisms have improved our understanding of the mechanisms by which genetic factors predispose for COPD. The beneficial effects of smoking cessation in slowing the decline in lung function and the progression of disease have been clearly established. Whether other factors such as mucus hypersecretion, respiratory infections and airway hyperreactivity contribute to disease progression independent of cigarette smoking is still being debated. There is new interest in dietary strategies to prevent or control COPD and preliminary information suggesting the usefulness of diets favoring antioxidant-rich foods. On the other hand several large, long-term, randomized, controlled clinical trials have failed to show a beneficial effect of either anticholinergics or corticosteroids in slowing the rate of decline in lung function in COPD. Corticosteroid treatment, however, appears to reduce the frequency of COPD exacerbations and there is some suggestion that it may also reduce the risk of death in patients with severe COPD.     

Chronic obstructive pulmonary disease and lung cancer: new molecular insights

Both chronic obstructive pulmonary disease (COPD) and lung cancer are major causes of death worldwide. In most cases this reflects cigarette smoke exposure which is able to induce an inflammatory response in the airways of smokers. Indeed, COPD is characterized by lower airway inflammation, and importantly, the presence of COPD is by far the greatest risk factor for lung cancer amongst smokers. Cigarette smoke induces the release of many inflammatory mediators and growth factors including TGF-β, EGFR, IL-1, IL-8 and G-CSF through oxidative stress pathways and this inflammation may persist for decades after smoking cessation. Mucus production is also increased by these inflammatory mediators, further linking airway inflammation to an important mechanism of lung cancer. A greater understanding of the molecular and cellular pathobiology that distinguishes smokers with lung cancer from smokers with and without COPD is needed to unravel the complex molecular interactions between COPD and lung cancer. By understanding the common signalling pathways involved in COPD and lung cancer the hope is that treatments will be developed that not only treat the underlying disease process in COPD, but also reduce the currently high risk of developing lung cancer in these patients.     

Pathogenesis of COPD

Chronic obstructive pulmonary disease (COPD) is characterized and defined by limitation of expiratory airflow. This can result from several types of anatomical lesions, including loss of lung elastic recoil and fibrosis and narrowing of small airways. Inflammation, edema, and secretions also contribute variably to airflow limitation. Smoking can cause COPD through several mechanisms. First, smoke is a powerful inducer of an inflammatory response. Inflammatory mediators, including oxidants and proteases, are believed to play a major role in causing lung damage. Smoke can also alter lung repair responses in several ways. Inhibition of repair may lead to tissue destruction that characterizes emphysema, whereas abnormal repair can lead to the peribronchiolar fibrosis that causes airflow limitation in small airways. Genetic factors likely play a major role and probably account for much of the heterogeneity susceptibility to smoke and other factors. Many factors may play a role, but to date, only alpha-1 protease inhibitor deficiency has been unambiguously identified. Exposures other than cigarette smoke can contribute to the development of COPD. Inflammation of the lower respiratory tract that results from asthma or other chronic disorders may also contribute to the development of fixed airway obstruction. COPD is not only a disease of the lungs but is also a systemic inflammatory disorder. Muscular weakness, increased risk for atherosclerotic vascular disease, depression, osteoporosis, and abnormalities in fluids and electrolyte balance may all be consequences of COPD. Advances in understanding the pathogenesis of COPD have the potential for identifying new therapeutic targets that could alter the natural history of this devastating disorder.     

吸烟引起慢性阻塞性肺疾病糖皮质激素抵抗的机制及应对策略

糖皮质激素（GC）在大部分支气管哮喘患者的治疗中取得了显著的疗效，然而对大多数COPD患者疗效欠佳。COPD发病的核心环节是慢性炎症反应，GC是体内最强大最广谱的抗炎物质，当GC对炎症反应的抑制作用下降，会导致炎症反应的持续，从而引起相应病理过程。因此，激素抵抗不仅仅是COPD患者治疗不佳的原因，它有可能直接参与了COPD的发病。本文对吸烟所致COPD引起GC抵抗的机制及目前可能采取的对策进行综述。     

Mast cells and COPD

The pathogenesis of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune response to the inhalation of toxic particles and gases. Although tobacco smoking is the primary cause of this inhalation injury, many other environmental and occupational exposures contribute to the pathology of COPD. The immune inflammatory changes associated with COPD are linked to a tissue-repair and -remodeling process that increases mucus production and causes emphysematous destruction of the gas-exchanging surface of the lung. The common form of emphysema observed in smokers begins in the respiratory bronchioles near the thickened and narrowed small bronchioles that become the major site of obstruction in COPD. The inflamed airways of COPD patients contain several inflammatory cells including neutrophils, macrophages, T lymphocytes, and dendritic cells. The relative contribution of mast cells to airway injury and remodeling is not well documented. In this review, an overview is given on the possible role of mast cells and their mediators in the pathogenesis of COPD. Activation of mast cells and mast cell signaling in response to exposure to cigarette smoke is further discussed.     

Decreased expression of antioxidant enzymes and increased expression of chemokines in COPD lung

The involvement of inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) has been investigated using samples from relatively central airways such as airway biopsies, but there have been fewer studies in the peripheral lung, which is thought to be the main site of the disease process. To determine the molecules that relate to the mechanisms underlying the pathogenesis of COPD, we evaluated the mRNA expression of inflammatory cytokines, chemokines, oxidant enzymes, antioxidant enzymes, proteinases and antiproteinases in peripheral lung tissues from 33 COPD and non-COPD subjects who were undergoing lung resection for lung cancer using an RT-PCR technique. Among the 42 studied candidate genes, the expressions of mRNA for catalase, glutathion S-transferase P1 (GSTP1), glutathion S-transferase M1 (GSTM1), microsomal epoxide hydrolase (mEPHX) and tissue inhibitor of metalloproteinase 2 (TIMP2) were significantly decreased in COPD lung tissues compared with those in non-COPD tissues, and most of these decreases were significantly correlated with the degree of airflow limitation. On the other hand, the expressions of mRNA for interleukin 1beta (IL-1beta), interleukin 8 (IL-8), growth-related oncogene-alpha (Gro-alpha) and monocyte chemotactic protein-1 (MCP-1) were significantly increased in COPD lungs. Most of these changes were also associated with cigarette smoking. These data suggest that an impairment of protective mechanisms against oxidants and xenobiotics, in addition to the upregulation of CXC- and CC-chemokines, may be associated with cigarette smoking and involved in the inflammatory process of COPD.     

Microsatellite DNA instability in COPD.

STUDY OBJECTIVES: Cigarette smoking is the prime cause of COPD; however, only a few smokers develop the disease. In a previous study, we demonstrated that microsatellite DNA instability (MSI) is a detectable phenomenon in sputum cells of COPD patients. Therefore, we hypothesize that this genetic alteration may indicate susceptibility to COPD. DESIGN: In order to investigate this hypothesis, we compared smokers who developed COPD with smokers who did not develop COPD (referred to as non-COPD smokers). SETTING: Seven highly polymorphic microsatellite markers were targeted on the DNA of sputum cells and of WBCs. PATIENTS AND PARTICIPANTS: We studied 60 non-COPD smokers and 59 severe COPD patients with a similar smoking history (mean +/- SD) of 48+/-25 and 54+/-33 pack-years, respectively (p = 0.77). Non-COPD smokers were tested once; COPD smokers were tested twice, with an interval of 24 months between tests. RESULTS: MSI was detected in 14 COPD patients (24%) but in none of the non-COPD smokers. In 10 COPD patients, MSI was exhibited by one microsatellite marker; in the remaining 4 COPD patients, MSI was exhibited by two different alleles. The most commonly affected marker was THRA1 on chromosome 17 (43%). No significant differences were found between MSI-positive and MSI-negative COPD patients for clinical or laboratory parameters, survival, and development of lung cancer. No change in the microsatellite alleles was found between the tests performed with a 24-month interval. CONCLUSIONS: This study demonstrated that MSI was found exclusively in the sputum cells of smokers with COPD. The results support the hypothesis that MSI could be part of the complex genetic basis of COPD, and it could be a marker of the genetic alteration caused by smoking that allows COPD to develop.     

Similar gene expression profiles in smokers and patients with moderate COPD

Chronic obstructive pulmonary disease (COPD) is characterized by multiple cellular and structural changes affecting the airways, lung parenchyma and vasculature, some of which are also identified in smokers without COPD. The molecular mechanisms underlying these changes remain poorly understood. With the aim of identifying mediators potentially implicated in the pathogenic processes that occur in COPD and their potential relationship with cigarette smoking, we evaluated the mRNA expression of genes involved in inflammation, tissue remodeling and vessel maintenance. Lung tissue samples were obtained from 60 patients who underwent lung resection (nonsmokers, n=12; smokers, n=12; and moderate COPD, n=21) or lung transplant (severe-to-very severe COPD, n=15). PCR arrays containing 42 genes coding for growth factors/receptors, cytokines, metalloproteinases, adhesion molecules, and vessel maintenance mediators were used. Smoking-induced changes include the up-regulation of inflammatory genes (IL-1β, IL-6, IL-8, CCL2, and CCL8) and the decreased expression of growth factor/receptor genes (BMPR2, CTGF, FGF1, KDR and TEK) and genes coding for vessel maintenance factors (EDNRB). All these genes exhibited a similar profile in moderate COPD patients. The up-regulation of MMP1 and MMP9 was the main change associated with COPD. Inflammatory genes as well as the endothelial selectin gene (SELE) were down-regulated in patients with more severe COPD. Clustering analysis revealed a closer relationship between moderate COPD and smokers than between both subsets of COPD patients for this selected set of genes. The study reveals striking similarities between smokers and COPD patients with moderate disease emphasizing the crucial role of cigarette smoking in the genesis of these changes, and provides additional evidence of the involvement of the matrix metalloproteinase's in the remodeling process of the lung in COPD.     

慢性阻塞性肺疾病的细胞与分子机制研究进展

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)以不完全可逆的气流受限为特征,它在世界范围内的高发病率和病死率是导致巨大经济和社会负担的主要原因.COPD肺部慢性炎症由炎症细胞及其分泌的细胞因子和趋化因子等相互作用而发生发展的,并可触发先天性和获得性免疫反应,进一步加重炎症反应.本文就炎症细胞及细胞因子在COPD形成机制中的作用,以及先天性和获得性免疫机制在COPD肺部炎症的作用作一综述,以期提高对本病发病机制的认识.     

Pathogenese der COPD

It is currently believed that the most important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD) is inflammation of the small airways caused by inhaled particles and gases. In this context, a disturbance of the physiological balance between proteases and antiproteases develops that may cause lung emphysema. Moreover, oxidative stress seems to be important, as it may enhance the inflammatory reaction. The development of emphysema may also involve a loss of alveolar cells by apoptosis. Finally, several studies have indicated that a systemic inflammation is induced by COPD that may be of relevance to the development of systemic components that are observed in COPD patients.