Pathogenesis of COPD. Part II. Oxidative-antioxidative imbalance.

Chronic obstructive pulmonary disease (COPD) represents a serious global health problem that affects the aged. This State of the Art article summarises previous studies on oxidative-antioxidative imbalance in patients with stable COPD or in acute exacerbations. Recent literature in this field reports conflicting findings. Several studies on markers of oxidative stress have demonstrated increased production of oxidants in exhaled air, breath condensates or induced sputum. The primary defence against oxidants is endogenous antioxidants, which are altered in COPD. Some studies have demonstrated a marked decrease in plasma antioxidant capacity, while other studies have shown opposite findings. A few studies have shown higher erythrocyte superoxide dismutase (SOD) activity in COPD patients and healthy smokers than those in healthy non-smokers. In contrast, we found no differences in erythrocyte SOD activity and elevated erythrocyte catalase activity in Chinese patients with COPD compared with healthy smokers matched for age and pack-years smoked. Possible reasons for such discrepancies could be related to differences in inter-individual variations in antioxidant capacity as a result of different populations and also differences in methodologies between studies.     

Pathogenesis of COPD. Part III. Inflammation in COPD.

Chronic obstructive pulmonary disease (COPD) is mostly caused by cigarette smoking and affects up to 25% of smokers. Air pollution and occupational exposure to dust and fumes can also induce COPD. COPD is characterised by airflow limitation that is not fully reversible and chronic inflammation of the lung. Most patients with COPD also have evidence of tissue remodelling in the smaller airways. How the different pathological features are linked remains unknown. The inflammation of the COPD lung is initially caused by cigarette smoke and the increased infiltration of immune cells into the lung, but it is not clear why the inflammation persists after smoking cessation, while other pathologies partly reverse. Furthermore, anti-inflammatory treatments are not very successful and only control the symptoms but do not cure the disease. Animal models suggest that the imbalance of proteases and antiproteases is central to the major pathologies in the COPD lung. However, this hypothesis was never fully confirmed in humans and may only explain the degenerative stage of the disease, emphysema. The role of tissue-forming cells in the pathogenesis of COPD has not been adequately studied and indicates a deregulated synthesis of growth factors and cytokines in COPD. Finally, recent studies indicate that alpha-1-antitrypsin activity plays a role in all forms of COPD.     

The biochemical pathogenesis of chronic obstructive pulmonary diseases: protease-antiprotease imbalance in emphysema and diseases of the airways

Emphysema is believed to result from destruction of elastic fibers due to an imbalance between proteases and their inhibitors in the lung. The imbalance can arise from a primary failure of secretion of the inhibitors, as occurs in hereditary alpha-1-protease inhibitor deficiency, or as the result of complex interactions of environmental agents with the lung. Environmental agents may produce their effects by stimulating degradation of elastic fibers by neutrophils and macrophages, damaging protease inhibitors by oxidative or proteolytic mechanisms or by impairing the biosynthetic repair of damage to the connective tissue. Protease excess has also been consistently observed in purulent sputum. Since experimentally administered proteases stimulate secretion of mucus and damage mucociliary clearance, protease-antiprotease imbalance might be involved in the pathogenesis of bronchitis and bronchiectasis as well as emphysema. Because the protease inhibitors of bronchial mucus are distinct from those of the acinar units, and no hereditary deficiencies are known, there is no direct proof of this hypothesis in man.     

Elastases and emphysema. Current assessment of the protease-antiprotease hypothesis

Many studies have been carried out in the past 10 yr dealing with the possible role of elastase in the pathogenesis of pulmonary emphysema. These include newer observations in animal models revealing augmentation of elastase-induced lesions by lathyrogens or by exposure to cigarette smoke. In general, the animal model experiments have focussed attention on repair-processes in the lung and shown that such processes may exert a major influence on the outcome of the initial proteolytic insult. Human studies exploring correlations between elastase levels in neutrophils or serum and development of disease have provided conflicting data; however, measurement of enzymes in pulmonary secretions have yielded more suggestive results. Assessments of lung elastase inhibitors in humans continue to support the importance of alpha-1-proteinase inhibitor in the protection of the lower respiratory tract, but newer information on locally produced, low molecular weight elastase inhibitors indicates that these, too, may play a significant role. Attempts have been made to link cigarette smoking to the development of emphysema at the chemical and cellular levels. These studies have focussed on: (1) the recruitment of elastase-producing leukocytes to smokers' lungs, (2) inactivation of lung elastase-inhibitors by tobacco products or by metabolites released from tobacco-stimulated lung cells, and (3) interference with elastin neosynthesis (repair) in the smoker. Additional information is also available concerning the biochemical properties of neutrophil and macrophage elastases, although it is still unclear which of these enzymes plays the predominant role in chronic lung injury associated with smoking. Perhaps the greatest advance in the emphysema field in recent years involves new discoveries concerning the structure and function of the alpha-1-proteinase (elastase) inhibitor. Applications of recombinant DNA technology and genetic engineering have made it possible to design modified inhibitors with striking new properties. These agents may enjoy significant clinical application in the not too distant future.     

COPD management. Part I. Strategies for managing the burden of established COPD.

Effective management of chronic obstructive pulmonary disease (COPD) is dependent on an accurate diagnosis and assessment of severity. COPD is a clinical diagnosis, based on a history of exposure to known risk factors and the presence of airway obstruction that is not fully reversible. Maximal therapy and support for smoking cessation should be offered to all patients. Symptoms may only develop when a significant loss of lung function has occurred, and the diagnosis is frequently made late in the course of the disease. Earlier diagnosis is dependent on a high index of suspicion, particularly in current and ex-smokers or those exposed to occupational dusts and indoor pollution, and accurate performance and interpretation of spirometry. Established COPD associated with symptoms should initially be treated with bronchodilators as needed, but long-acting bronchodilators should be used when symptoms persist and inhaled corticosteroids added for moderate to severe airflow limitation, particularly when associated with exacerbations. Combination long-acting bronchodilators and inhaled corticosteroids reduce the exacerbation rate and improve the quality of life and symptoms, but they have not been shown to improve survival. Exacerbations are associated with worsening health status and can be managed effectively at home. When symptoms worsen despite optimal treatment for exacerbations, hospital admission is necessary. Non-invasive ventilation has reduced the need for mechanical ventilation, but hospital admission and respiratory failure are associated with a significantly worse prognosis. Pulmonary rehabilitation plays an important role in improving exercise capacity at all severities of COPD, and should be widely available.     

The extent of emphysema in patients with COPD

Background and Aims: The global initiative for COPD (GOLD) adopted the degree of airway obstruction as a measure of the severity of the disease. The objective of this study was to apply CT to assess the extent of emphysema in patients with chronic obstructive pulmonary disease (COPD) and relate this extent to the GOLD stage of airway obstruction. Materials and Methods: We included 209 patients with COPD. COPD was defined as FEV₁/FVC < 0.70 and no reversibility to β₂‐agonists. All patients were current smokers with a smoking history of ≥20 pack‐years. Patients were assessed by lung function measurement and visual and quantitative assessment of CT, from which the relative area of emphysema below ?910 Hounsfield units (RA‐910) was extracted. Results: Mean RA‐910 was 7.4% (n = 5) in patients with GOLD stage I, 17.0% (n = 119) in stage II, 24.2% (n = 79) in stage III and 33.9% (n = 6) in stage IV. Regression analysis showed a change in RA‐910 of 7.8% with increasing severity according to GOLD stage (P < 0.001). Combined visual and quantitative assessment of CT showed that 184 patients had radiological evidence of emphysema, whereas 25 patients had no emphysema. Conclusion: The extent of emphysema increases with increasing severity of COPD and most patients with COPD have emphysema. Tissue destruction by emphysema is therefore an important determinant of disease severity in COPD. Please cite this paper as: Shaker SB, Stavngaard T, Hestad M, Bach KS, Tonnesen P and Dirksen A. The extent of emphysema in patients with COPD. The Clinical Respiratory Journal 2009; 3: 15–21.     

The protease-antiprotease balance within the human lung: Implications for the pathogenesis of emphysema

Critical elements of the mechanisms of emphysema remain to be clarified. However, taken together, the existing evidence supports the concept that alveolar matrix destruction ensues as the regulatory interplay between oxidant and protease expression is subverted. The final common pathway of matrix destruction links the inherited and acquired forms of emphysema through the ultimate expression of unimpeded neutrophil elastase.     

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.     

Orbital emphysema in COPD with bronchopleural fistula

Orbital emphysema is usually a benign, self-limited condition. Intraorbital extension of the entrapped air in the absence of an orbital fracture is extremely rare. Although benign, a careful periodic monitoring of intraocular pressure, optic nerve examinations, and prompt management are warranted in order to prevent tension pneumoobitus secondary to increasing intraorbital pressure by the orbital air.     

The role of NETT in emphysema research

Lung volume reduction surgery (LVRS) is one of a long lineage of surgical approaches to emphysema. The reintroduction of this operation in the mid-1990s led to great controversy over the value of the procedure and its long-term outcomes. The National Emphysema Treatment Trial (NETT) represented an historical scientific collaboration of the National Institutes of Health (NIH), the Centers for Medicare and Medicaid Services (CMS), and the Agency for Health Research and Quality (AHRQ). NETT was designed primarily as a pivotal surgical clinical trial, but also incorporated data collection to inform health policy and cost-benefit analyses. NETT faced challenges that included practical and ethical matters, statistical design and analysis issues, and intense public and political scrutiny. The study design required the development of methods for pulmonary rehabilitation, lung imaging, and exercise testing that have become templates for current clinical and research practice. During the course of the trial, the confidential deliberations of the Data and Safety Monitoring Board (DSMB) played an important role in the ultimate success of the trial and protection of research participants. Because of the importance of the NETT outcomes, the results were disseminated to the medical community and transformed into health policy in a rapid and efficient manner. In many ways, the story of NETT serves as a model for evaluation of new surgical approaches to chronic diseases.     

The role of oxidative processes in emphysema

Elastase/elastase inhibitor imbalance in the lung has been implicated in the pathogenesis of pulmonary emphysema. In light of this, it may be significant that the activity of two major elastase inhibitors, alpha 1-proteinase inhibitor (alpha 1-antitrypsin, alpha 1Pi) and bronchial mucous proteinase inhibitor, can be decreased by oxidizing agents. The effect can be observed with ozone, substances present in cigarette smoke, and oxygen metabolites generated by lung macrophages as well as peroxidative systems released by other phagocytic cells. Thus alpha 1Pi recovered from lung washings of cigarette smokers has only half the predicted normal activity per mg inhibitor and contains 4 moles of methionine sulfoxide (oxidized methionine) per mole of inactive inhibitor. By contrast, alpha 1Pi purified from nonsmokers' lung washings is fully active and contains only native methionine. At the same time, lung washes from some smokers show significantly greater hydrolytic activity against a specific synthetic elastase substrate than do lung washes of nonsmokers. These findings suggest that some smokers may develop an acquired imbalance between elastase and elastase inhibitor in their lungs, favoring activity of the enzyme. In addition to the potential effect of cigarette smoking on lung elastase/elastase inhibitor balance, smoking also may interfere with elastin repair mechanisms. Specifically, acidic water-soluble gas phase components of cigarette smoke prevent synthesis of desmosine cross-links during elastinogenesis in vitro. This report will attempt to correlate the foregoing information on biochemical changes in the lung induced by cigarette smoking with the development of emphysema in the smoker.     

Pathogenesis and pathology of COPD

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation. Since flow is the result of a driving pressure that promotes flow and of an opposing resistance that contradicts it, the reduction in flow observed in COPD has two main components: increased resistance, which is due to airway obstruction, and a loss of the elastic recoil pressure of the lung, which is due to parenchymal destruction. Although it has long been known that the major site of increased resistance in COPD is the peripheral airways, recent studies have shown that central airways are involved in the disease as well. The purpose of this review is to describe the major structural and cellular changes present in peripheral airways, central airways and lung parenchyma of patients with COPD, and to underline the possible mechanisms contributing to airflow limitation in these subjects.     

The association between small airway obstruction and emphysema phenotypes in COPD

BACKGROUND: Airflow limitation in COPD is due to a variable combination of small airway obstruction and centrilobular emphysema (CLE) and/or panlobular emphysema (PLE), but the relationship between these three different phenotypes is poorly understood. This study compares the severity of small airway obstruction in both forms of emphysema and determines its relationship with FEV(1). METHODS: We compared the lung histology of nonsmoking control subjects without emphysema (n = 10) to that of patients with CLE (n = 30) and PLE with (n = 8) and without alpha(1)-antitrypsin (AAT) deficiency (n = 11). The degree of airspace enlargement was measured using the mean interalveolar wall distance (IAWD) [mean linear intercept, Lm], and the evenness of airspace destruction was assessed by the coefficient of variation (CV) of the IAWD. The severity of small airway obstruction was determined by dividing total wall area by the length of the basement membrane to obtain wall thickness. RESULTS: Lm was greater in all three subgroups of emphysema than in control subjects, and in AAT deficiency than in PLE or CLE. The CV of IAWD was greater in AAT deficiency and CLE than in control subjects and in CLE than in AAT deficiency or PLE. Although small airway wall thickness was greater in CLE and PLE with AAT deficiency than in control subjects, the association between wall thickness and both Lm and FEV(1) was observed only in CLE. CONCLUSIONS: Small airway wall thickening occurs in CLE and PLE with AAT deficiency but is more closely associated with degree of emphysema and airflow limitation in CLE.