Pathogenesis of chronic obstructive pulmonary disease (COPD)

Pathogenesis of chronic obstructive pulmonary disease (COPD)

Clinical and Applied Immunology Reviews 5 (2005) 339–351 Review Pathogenesis of chronic obstructive pulmonary disease (COPD) Massoud Daheshia, PhD* ...

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Clinical and Applied Immunology Reviews 5 (2005) 339–351

Review

Pathogenesis of chronic obstructive pulmonary disease (COPD) Massoud Daheshia, PhD* Lovelace Respiratory Research Institute and the Department of Pharmacy and Pathology, School of Medicine, University of New Mexico, 2425 Ridgecrest Dr. SE, Albuquerque, NM 87108-5127, USA Received 1 June 2005; received in revised form 29 August 2005; accepted 13 September 2005.

Abstract Chronic obstructive pulmonary disease (COPD) could develop following long-term exposure of individuals to cigarette smoke, toxic gases, and particulate matter, resulting in airway flow limitation, pulmonary failure, multiple systemic effects, and, eventually, death. The disease is associated with pulmonary inflammation with its own specific characteristics, and could be exacerbated by multiple factors such as microbial infection. COPD is chronic and progressive in nature, and multiple pulmonary inflammatory cells are detected at different stages of the disease, with a possible network of interactions with parenchymal cells. The pathological changes in the lung of COPD patients are characterized by an excess of extracellular matrix deposition, yet, loss of extracellular matrix in alveoli, increased thickness of airway walls, mucus hypersecretions, and destruction of alveolar septae, resulting in narrowing of airway diameters, reduced functional lung parenchyma, and decreased elastic tethering forces to maintain airway patency. Multiple factors, such as inflammatory cytokines, proteolytic proteinases, and oxidative stress molecules are suspected to be responsible, each at some degree, for these structural changes leading to airway obstruction. Because not everyone exposed to cigarette smoke will develop the disease, it is reasonable to think that multiple risk factors are involved and that COPD could be developed along a variety of pathways. Our current understanding of pulmonary changes associated with COPD, its similarity and differences with asthma, the nature of inflammatory cells associated with the disease, and the capacity of different molecules to induce a

Abbreviations: AHR, airway hyperresponsiveness; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IL, interleukin; MCP-1, monocyte chemoattractant protein-1; MMP, matrix metalloproteinase; TNFa, tumor necrosis factor alpha; b, beta. * Corresponding author. Tel.: C1 505 348 9618; fax: C1 505 348 8567. E-mail address: [email protected] (M. Daheshia). 1529-1049/05/$ – see front matter Ó 2005 Elsevier Inc. All rights reserved. doi: 10.1016/j.cair.2005.09.003

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variety of these structural alterations are discussed to advance a cellular and molecular look at the pathogenesis of COPD. Ó 2005 Elsevier Inc. All rights reserved. Keywords: COPD; Lung; Inflammation; Asthma; Epithelium; Exacerbation

1. Introduction The worldwide incidence of chronic obstructive pulmonary disease (COPD) is increasing; it is the fourth most common cause of death in the United States and is expected to be the third most common cause of death by 2020 [1]. In the United States alone, the direct and indirect costs of managing COPD exceed 32 billion dollars annually [2]. The disease is mainly caused by long-term exposure of individuals to cigarette smoke, environmental toxins, and air pollutants. Although cigarette smoking is the major cause of the disease, as many as 20% of the patients who have COPD or die from the illness are lifelong nonsmokers [3]. COPD is manifested as a not fully reversible decrease in airway flow, causing dyspnea, lung failure, and, eventually, death [4]. The airflow limitation is due to varying combinations of destruction and remodeling of the airways and the lung parenchyma [5]. Although lung function naturally decreases as an individual ages, this decrease is much more accelerated in COPD patients (Fig. 1). The illness is chronic and progressive in nature and influenced by several factors such as an individual’s genetic makeup, number of years of exposure to smoke, quantity of cigarettes smoked, air pollution, and infection. The disease is typically diagnosed in individuals of more than 40 years, which perhaps indicates a long-term exposure to toxin. Although the number of people affected by COPD is increasing worldwide, it is assumed that this number is much higher than estimated, because the disease is usually detected when it is clinically advanced and not during its long initial phase. The disease

Fig. 1. The normal lung function capacity, in a 25-year-old adult, declines over time (as measured here by FEV1). However, this decline is much more accelerated in an adult exposed to toxins such as cigarette smoke. This rapid decline could, however, slow down if the exposure to toxin is stopped.

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has its roots decades before the onset of symptoms [6]. Cough and an increase in sputum can precede the decrease in lung function, although not all patients show these manifestations, and not all individuals with cough and productive sputum will develop the disease. The clinical manifestations and the severity of the disease can vary between individuals. The global initiative for chronic obstructive lung disease has recently classified the disease, mainly based on spirometry, on a scale of 0–4 with grade 4 as the most severe [7], where the patients show more than 70% reduction in forced expiratory volume in 1 s (FEV1) (Table 1). 2. Pathophysiology of COPD The pulmonary manifestation of COPD, such as decrease in FEV1 compared to predicted FEV1 and a reduction in the percentage of FEV1/FVC (forced vital capacity), could be due to at least two different pathological manifestations, each with a distinct structural expressiondchronic bronchitis and emphysema. Chronic bronchitis is defined by the presence of a mucus-producing cough most days of the month, 3 months a year for 2 successive years. Thus, the disease affects the airways causing stimulation of mucus production and an increase in the thickness of the airway wall, which is caused by hypertrophy/hyperplasia of the epithelium and/or by inflammatory cells invading the bronchial tubes. The thickened wall, hypersecretion, and an increase in airway mucus along with epithelial debris could lead to narrowing of the airway diameter and obstruction of the air passage [8]. Emphysema, evidenced by parenchymal damage, on the other hand, displays as destruction of the alveolar septae, leading to enlargement of distal air spaces, a decrease in alveolar elastic recoil, decreased traction support of small airway lumens, and impaired exhalation Table 1 GOLD classification of COPDa Stage

COPD definition

Severity

0 1

At risk Mild

2

Moderate

3

Severe

4

Very severe

Chronic cough and sputum production/normal lung function FEV1 > 80% predicted FEV1/FVC ! 70% 50% < FEV1 ! 80% predicted FEV1/FVC ! 70% 30% ! FEV1 ! 50% predicted FEV1/FVC ! 70% FEV1 ! 30% predicted FEV1/FVC ! 70% Or FEV1 ! 50% predicted plus chronic respiratory failure FEV1/FVC ! 70%

a

The global initiative for chronic obstructive lung disease (GOLD) has classified the severity of COPD on a scale of 0–4. Individuals at risk (stage 0) have a normal spirometry (normal FEV1 and FEV1/FVC) but exhibit chronic symptoms such as cough and productive sputum. However, not all COPD patients show chronic symptoms and not all individuals with chronic symptoms will develop the disease. Stage 4 has been classified as the most severe.

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[9]. Because capillary-rich alveolar walls are also destroyed in areas of emphysema, these enlarged redundant air spaces have very high ventilation/perfusion ratios, creating physiologic dead spaces [10]. One physiological outcome of these structural changes is gas trapping due to the decreased elastic tethering forces required to maintain airway patency during the expiratory phase. In emphysema, because of increased residual volume, inspired gas is always mixed with less oxygenated air, and pulmonary oxygenation is decreased. Although COPD is primarily a pulmonary illness, the disease has also systemic manifestations and, like most complex disorders, it affects far more than a single organ system. For example, at the late stage of the disease muscle weakness and weight loss [11], cardiovascular disease [12], osteoporosis [12], heart enlargement, and depression [13] have been associated with COPD by substantially limiting the daily activities of the patients, leading to immobility, social isolation, and a poor quality of life.

3. Nature of pulmonary inflammatory responses in COPD 3.1. Neutrophils/macrophages COPD is characterized by chronic inflammation, thus the inhaled toxin could induce pulmonary inflammatory reactions [14]. For example, exposure of the lung to cigarette smoke causes an influx of inflammatory cells [15], and the bronchoalveolar lavage fluid of smokers contains increased numbers of neutrophils and macrophages [16]. Indeed, an increase in the number of pulmonary neutrophils and macrophages has been reported in COPD patients and associated with an increase in inflammatory mediators and adhesion molecules. Additionally, it has been reported that the inflammatory response in the lungs of COPD patients increases with the severity of the disease and that the inflammatory response persists even after the smoking ceases [17]. For example, Turato et al. [18] reported that as compared with smokers with mild or no COPD, smokers with severe COPD had an increased number of leucocytes in the small airways, which showed a positive correlation with the radiological score of emphysema and a negative correlation with the values of FEV1. Cosio et al. [19] reported significantly higher numbers of neutrophils and macrophages in the bronchoalveolar lavage fluid of smokers and COPD patients compared to nonsmokers. In addition, Baraldo et al. [20] showed that smokers with COPD had an increased number of neutrophils in the airway smooth muscle compared with nonsmokers. Smokers with normal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesser extent. When all the subjects were analyzed as one group, neutrophilic infiltration was inversely related to FEV1. Additionally, Keatings et al. [21] found a significant increase in neutrophils and increased concentrations of tumor necrosis factor alpha (TNFa) and interleukin (IL)-8 in the patients with COPD compared with the smoking and nonsmoking control subjects. The role of macrophages in the pathogenesis of COPD has been highlighted by Cosio et al. [19] who reported that alveolar macrophages from smokers and COPD patients showed increased release of IL-8 and TNFa, and by Finkelstein et al. [22] who described that the extent of lung destruction during the disease was directly related to the number of alveolar macrophages per cubic millimeter.

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Proteinase/antiproteinase imbalance [23] and oxidant/antioxidant disparity [24] have been advanced to account for the pathology of COPD. Both neutrophils and macrophages have the capacity to release an array of bioreactive oxidant [25] and proteinases [26] that can induce pulmonary inflammation, parenchymal destruction, and structural changes associated with COPD. For example, Finlay et al. [27] detected elevated levels of matrix metalloproteinase (MMP)-l and -9 in macrophages from emphysematous patients vs. those from control subjects; and MMP-9 complexes were secreted by emphysematous patients but not by control subjects. Furthermore, Lim et al. [28] reported that cultured airway macrophages from smokers released greater amounts of MMP-9 at baseline and in response to IL-1 beta (b) and lipopolysaccharide than did those of nonsmokers. And Segura-Valdez et al. [29], who also analyzed the lungs of COPD patients, reported an increase in the levels of MMP-8 and -9 associated with neutrophils. Additionally, Molet et al. [30] reported an increase in MMP12 in the lungs of COPD patients. The authors reported that macrophages in BALF samples and in bronchial biopsies expressed a higher amount of MMP-12 than in normal subjects. Thus, macrophages and neutrophils could readily be involved in COPD, at least partly through release of free radical/oxidative stress molecules and proteinases. Interestingly, Kim and Nadel [31] have suggested that the increased necrosis of neutrophils in the airway lumen of COPD patients could lead to discharge of elastase and reactive oxygen species causing mucus hypersecretion. 3.2. Airway epithelium Airway epithelium has also been suggested as an initiator of COPD by generating multiple mediators. For example, Puljic and Pahl [32] described release of several chemokines by lung epithelial cells due to cigarette smoke, and these inductions were steroid resistant. It has also been shown that exposure of human airway epithelial cells to cigarette smoke induces activation of P38 and nuclear factor kappa beta and releases IL-6 and IL-8 [33]. Additionally, Fuke et al. [34] reported that airway epithelium from smoker with COPD produced higher amount of chemokines such as IL-8, macrophage inflammatory protein-1 alpha, and monocyte chemoattractant protein-1 (MCP-1) when compared with smokers without airflow limitation or never smokers. 3.3. T lymphocytes An increase in T-cells has also been reported in the airways and lung parenchyma of COPD patients with a predominance of CD8 cells [35]. For example, Hogg et al. [17] reported the importance of inflammation in small airways as a determinant of the progression and severity of the disease and found an increase in the absolute number of CD8 cells as the disease progressed. Interestingly, the increase in CD8 cells was not limited to pulmonary tissues, as there was an increase in the number of these cells in the paratracheal lymph nodes from smokers with COPD [36]. Although the nature of antigen specificity of these T-cells is not clear, Grumelli et al. [37] reported that T-cells isolated from lung biopsies of COPD patients displayed activation phenotype. The invading lymphocytes associated with COPD could be a source of multiple cytokines and apoptotic proteins. For example, Setta et al.

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[38] suggested that cytotoxic CD8 cells in the pulmonary parenchyma may contribute to the parenchymal destruction found in COPD by release of granzymes and perforins. Furthermore, the CD8 lymphocytes could activate the death signal in airway epithelial cells by releasing TNFa. Interestingly, Miotto et al. [39] reported that CD8 in the central airways of smokers with chronic bronchitis are a source of IL-4 and IL-13, leading to mucus hypersecretion, which occurs in chronic bronchitis. Thus, a cellular mechanism can be conceived where toxin exposure activates the alveolar macrophages and airway epithelium, leading to recruitment of more inflammatory cells that have the potential to destroy lung parenchyma and induce pulmonary changes (Fig. 2).

Fig. 2. The molecular events and cellular involvements during the pathogenesis of COPD. The toxin exposure of the lung could activate the alveolar macrophages and also the airway epithelium to generate chemotactic factors that, once released, induce a cascade of events leading to infiltration of the lung with hematopoietic cells that, in turn, directly or in association with aerosol stimulate the release of several destructive factors to damage the pulmonary architecture. Additionally, infiltrating cells could themselves be a new source of chemotactic factors, which could sustain the inflammatory reactions in the lung, leading to a chronic and progressive disease.

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4. COPD exacerbation Exacerbation of COPD is defined as a sustained worsening of the patient’s condition, from the stable and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication [40]. For example, a change in the patient’s baseline dyspnea, cough, or sputum beyond day-to-day variability that is sufficient to warrant a change in disease management, such as hospitalization, could be considered as an exacerbation. It is assumed that most of the morbidity, mortality, and healthcare costs of patients with COPD are related to the exacerbation of COPD, with more than 1 million emergency department visits per year [40]. Although the etiology of COPD exacerbations has not been completely clarified, there is strong evidence for bacterial involvement in almost half of the exacerbations [41]. In addition, viral infection plays a substantial role in these processes and could account for one third of these exacerbations [42]. It also has been reported that viral infection may impair host defense mechanisms, which could lead to increased colonization or infection with bacteria [43]. Bacterial, viral, and atypical pathogens, either alone or in concert, have been implicated in inducing the majority of acute exacerbations [44]. The inflammatory component of exacerbation maybe of relevance because inhaled steroids (fluticasone propionate) were effective in preventing exacerbation of COPD [45]. Although there are few data available regarding cellular events during COPD exacerbation, it has been reported that the changes in inflammatory cells during exacerbation of COPD are the same as those observed during exacerbation of asthma [46]. For example, Saetta et al. [46] reported that subjects with chronic bronchitis during exacerbations had around 30-fold more eosinophils in their bronchial biopsies than did those examined under baseline conditions. To a lesser extent, the numbers of neutrophils, T lymphocytes, and TNFa positive cells were also increased during exacerbations. In another study, Saetta et al. [47] showed that the degree of eosinophilia was similar in bronchial biopsies of asthmatic patients and patients with exacerbation of chronic bronchitis. In support and extent of these studies, Zhu et al. [48] reported that following an exacerbation, regulated on activation, normal T-cell expressed and probably secreted expression was upregulated and strongly expressed in the surface epithelium and subepithelium, which could account for increased numbers of eosinophils. However, both groups of investigators reported that IL-5 expression was not augmented during exacerbation vs. control. Thus, the quality of inflammatory response could be somehow specific to COPD exacerbation. 5. Risk factors for COPD Although toxin exposure is the main risk factor for developing COPD, not all individuals exposed to aerosol toxins develop the disease. For example, it is estimated that only around 20–40% of smokers will progress into COPD, and some smokers will not show any pathological signs [6,7]. Thus, it is postulated that other risk factors are involved in the initiation and progression of the illness. Genetic makeup and airway hyperreactivity (AHR) are advanced as risk factors for COPD in addition to toxin exposure. For example, alpha-1 antitrypsin deficiency leads to emphysema, and smoking accelerates the decline in lung

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functions [49]. Also, Celedon et al. [50] recently reported three single nucleotide polymorphisms among smokers in the COPD cases compared to control subjects. However, it is difficult to evaluate the absolute relevance of these studies because single nucleotide polymorphisms associated with COPD have been identified in more than 25 genes [51]. Additionally, it has been postulated that smokers with increased AHR develop COPD faster compared to smokers with normal AHR; and AHR to methacholine or histamine has been reported in COPD patients [52]. In a longitudinal study, Silva et al. [53] reported that active asthmatics had more than a 10-times higher risk for acquiring symptoms of COPD. The authors suggested a significant association between asthma diagnosis and the subsequent development of COPD. It is interesting to note that as early as the 1960s, Orie [54] advanced the idea of a relationship between COPD and asthma, which is known as the Dutch hypothesis. Thus, it is possible to think of the disease in a context of a 2-hit model, such as toxin exposure/genetic susceptibility or toxin exposure/preexisting pulmonary disorder. 6. Noticeable differences between COPD and asthma For a long time the misdiagnoses associated with COPD have been mainly because of its overlap with other pulmonary illnesses such as asthma. In both diseases the airflow is limited; there is presence of pulmonary inflammation, mucus secretion, and structural damages [7]. Many therapies that have been successfully used to treat asthma, such as bronchodilators, have also been used to treat COPD [55]. Both diseases appear to be heterogeneous in nature and caused by multiple factors. Fabbri et al. [56] reported that subjects with a history of asthma had a similar degree of fixed airway flow obstruction and AHR. Although COPD has several similarities with asthma, especially with severe asthma, as a whole it has its own specific cellular characteristics and structural modifications (Table 2). For example, even if Table 2 Characteristics of asthma compared to COPDa Parameters

Asthma

COPD

Airflow limitation Parenchymal destruction Target population Increased incidence Steroid sensitive Effector cells

Reversible No Children/adults Mostly western countries CC Eosinophils Mast cells Th2 cells IL-4 IL-5 IL-13 Most of the cases Th2 and Treg dysregulation

Not fully reversible Yes Middle/later life adults Worldwide C/ÿ Neutrophils Macrophages CD8 cells TNFa MMPs Oxidative stress molecules Unknown Proteinase/oxidative stress involvement

Effector molecules

Specific antibody Proposed mechanism a

Undeniably, COPD and asthma have several common features, and it is reasonable to think that increases in airway responsiveness could be a risk factor for COPD. However, it is helpful for diagnosis and appropriate treatment to characterize some dissimilarity between the two diseases, even though these differences could not be absolute in all cases.

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airflow limitation occurs in both diseases, in most cases of asthma this is a reversible phenomena; however, in the case of COPD, airflow limitation is not fully reversible. Atopic asthma requires a sensitization step leading to expansion of specific immune cells and generation of specific antibodies; however, it is not clear if COPD requires this step and if specific antibodies are generated during the illness. Inflammatory cells involved in pathogenesis of asthma are mainly eosinophils, mast cells, and Th2 cells [57]; but in COPD, neutrophils, macrophages, and CD8 are the major players. The nature of pathogenic molecules is substantially different within the two diseases: IL-4, IL-5, and IL-13 in asthma, and TNFa, MMPs, and oxidative stress proteins in COPD. Although pulmonary structural changes are associated with both illnesses, parenchymal destruction is almost exclusively present in COPD and not in asthma. Additionally, asthma is much more sensitive to steroid treatment than COPD [58], revealing that there are qualitative differences in the nature of their inflammatory responses. In addition, the target populations are different for each disease asthma can strike almost everyonedchildren and adults at any agedhowever, COPD mainly affects adult populations of more than 40 years [8]. Also, the incidence of both diseases is increasing, asthma is mainly increasing in western countries, but COPD is rising worldwide. The proposed underlying mechanisms of the disease are also differentdderegulation of Th2/Treg cells in the case of asthma and proteinase/oxidative stress involvement for COPD. Thus even with high similarity in the lung mechanics of COPD and asthma patients, it is conceivable to assess specific parameters. Based on their studies, Fabbri et al. [56] suggested that noninvasive measurements of eosinophils in sputum and exhaled NO might be clinically useful in assessing the relative contributions of asthma and COPD in patients without a clear clinical history.

7. Conclusion Although the pathophysiology of COPD is relatively well described, the steps in the initiation and progression of the disease are much less clear. It is generally well accepted that an inflammatory component is associated with the illness, and that inflammatory cells are present at different pulmonary compartments following chronic exposure to toxin and, additionally, their presence is, in some cases, persistent even following cessation of pulmonary exposure to toxins. But what the relative importance of inflammatory cells vs. parenchymal cells is regarding pathogenesis of COPD is not clearly defined. For example, it is massively reported that airway epithelial cells have the capacity to express and release a variety of molecules with potential capacity to be involved at different stages of the disease [59]; but at a level of cell-to-cell comparison, how much epithelial cells are contributing to the pathogenic processes compared to inflammatory cells is less obvious. Also, because COPD is often diagnosed at the advanced stages, it is not apparent if the initial structural changes are also dependent on inflammatory cells or the toxin/parenchyma interactions are enough for the early events. Exposure to toxins is a major risk factor for the development of the disease but it is also apparent, because not everyone exposed to toxin will develop COPD, that several other risk factors are involved. Genetic factors are obviously implicated in the susceptibility to disease, and several single nucleotide polymorphisms have been reported to be associated with the

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illness receptiveness, but experimental data confirming a direct implication of these single nucleotide polymorphisms are still lacking. Microbial infections are also being considered as the potential risk factors. However, it is not entirely clear what roles are being played by the pathogens in the initiation of the disease and its maintenance. For example, what are the implications of early life exposure to pathogen on the subsequent development of the disease and its initiation? Although it is well established that the infection is a risk factor for the exacerbation of COPD, we do not know at present if the nature of immune response subsequent to pathogen infection is a determinant factor in the COPD exacerbation. It is also becoming more evident that some degree of specificity to inflammatory responses is occurring during the development of COPD. The inflammatory responses in these processes are somehow persistent [17], leading to the concept that the nature of inflammation could be different compared to the other chronic pulmonary disorders. For example, chromatin structural alterations have recently been reported following cigarette smoke exposure [60], which could, by some means, be a plausible explanation for abnormal overexpression of several proteins during the illness. Thus, new sets of therapy need to be developed to overcome these genetics and epigenetic alterations that could eventually occur during pathogeneses of COPD, leading to the notion that some degree of similarity could be present with the oncogenic processes of lung cancer. It is also crucial to identify diagnostic markers that might allow the physicians and researchers to detect the disease at its early stages, follow the progression of COPD, and possess the tools for monitoring efficacy of therapeutic treatments at different stages. Although the assessment of airflow is crucial in establishing the diagnosis of COPD, it is becoming evident that the chance of success is much greater if the appropriate treatments are undertaken before deteriorations of lung mechanics at a time when the nonfully reversible changes could have already occurred. Thus, looking at the disease from different angles, considering that the illness could have multiple pathways of progression, developing several different approaches to tackle it might allow us to have better opportunities to overcome the increasing trend in the incidence of COPD. References [1] Barnes PJ. Small airways in COPD. N Engl J Med 2004;350(26):2635–7. [2] Mapel D, Chen JC, George D, Halbert RJ. The cost of chronic obstructive pulmonary disease and its effects on managed care. Manag Care Interface 2004;17(4):61–6. [3] Rennard SI. Looking at the patientdapproaching the problem of COPD. N Engl J Med 2004;350(10): 965–6. [4] Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med 2004; 350(26):2689–97. [5] Rutgers SR, Timens W, Kauffman HF, Postma DS. Markers of active airway inflammation and remodelling in chronic obstructive pulmonary disease. Clin Exp Allergy 2001;31(2):193–205. [6] Anto JM, Vermeire P, Vestbo J, Sunyer J. Epidemiology of chronic obstructive pulmonary disease. Eur Respir J 2001;17(5):982–94. [7] Fabbri LM, Kurd SS. GOLD Scientific Committee. Global strategy for the diagnosis, management and prevention of COPD: 2003 update. Eur Respir J 2003;22(1):1–2.

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[8] Pauwels RA, Buist AS, Ma P, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001;163(5):1256–76. [9] Snider GL. Chronic obstructive pulmonary disease: a definition and implications of structural determinants of airflow obstruction for epidemiology. Am Rev Respir Dis 1989;140(3 Pt 2):S3–8. [10] Maxfield RA. New and emerging minimally invasive techniques for lung volume reduction. Chest 2004; 125(2):777–83. [11] Berry JK, Baum C. Reversal of chronic obstructive pulmonary disease-associated weight loss: are there pharmacological treatment options? Drugs 2004;64(10):1041–52. [12] Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59(7):574–80. [13] Fehrenbach C. NICE guidelines for chronic obstructive pulmonary diseaseda review. Nurs Times 2004; 100(24):48–51. [14] Barnes PJ. New treatments for COPD. Nat Rev Drug Discov 2002;1(6):437–46. [15] Stringer KA, Freed BM, Dunn JS, Sayers S, Gustafson DL, Flores SC. Particulate phase cigarette smoke increases MnSOD, NQO1, and CINC-1 in rat lungs. Free Radic Biol Med 2004;37(10):1527–33. [16] Saetta M. Airway inflammation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999 Nov;160(5 Pt 2):S17–20. [17] Hogg JC, Chu F, Utokaparch S, Woods R, Elliott WM, Buzatu L, et al. The nature of small-airway obstruction in chronic obstructive pulmonary disease. N Engl J Med 2004;350(26):2645–53. [18] Turato G, Zuin R, Miniati M, Baraldo S, Rea F, Beghe B, et al. Airway inflammation in severe chronic obstructive pulmonary disease: relationship with lung function and radiologic emphysema. Am J Respir Crit Care Med 2002;166(1):105–10. [19] Cosio BG, Tsaprouni L, Ito K, Jazrawi E, Adcock IM, Barnes PJ. Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 2004;200(5):689–95. [20] Baraldo S, Turato G, Badin C, Bazzan E, Beghe B, Zuin R, et al. Neutrophilic infiltration within the airway smooth muscle in patients with COPD. Thorax 2004 Apr;59(4):308–12. [21] Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factoralpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153(2):530–4. [22] Finkelstein R, Fraser RS, Ghezzo H, Cosio MG. Alveolar inflammation and its relation to emphysema in smokers. Am J Respir Crit Care Med 1995;152(5 Pt 1):1666–72. [23] Turino GM. The origins of a concept: the protease-antiprotease imbalance hypothesis. Chest 2002;122(3): 1058–60. [24] Macnee W, Rahman I. Oxidants and antioxidants as therapeutic targets in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999;160(5 Pt 2):S58–65. [25] Rahman I, MacNee W. Lung glutathione and oxidative stress: implications in cigarette smoke-induced airway disease. Am J Physiol 1999 Dec;277(6 Pt 1):L1067–88. [26] Daheshia M. Therapeutic inhibition of matrix metalloproteinases for the treatment of chronic obstructive pulmonary disease (COPD). Curr Med Res Opin 2005;21(4):587–94. [27] Finlay GA, Russell KJ, McMahon KJ, D’arcy EM, Masterson JB, Fitzgerald MX, et al. Elevated levels of matrix metalloproteinases in bronchoalveolar lavage fluid of emphysematous patients. Thorax 1997;52(6): 502–6. [28] Lim S, Roche N, Oliver BG, Mattos W, Barnes PJ, Chung KF. Balance of matrix metalloprotease-9 and tissue inhibitor of metalloprotease-1 from alveolar macrophages in cigarette smokers. Regulation by interleukin-10. Am J Respir Crit Care Med 2000;162(4 Pt 1):1355–60. [29] Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal cell death in COPD. Chest 2000;117(3):684–94. [30] Molet S, Belleguic C, Lena H, Germain N, Bertrand CP, Shapiro SD, et al. Increase in macrophage elastase (MMP-12) in lungs from patients with chronic obstructive pulmonary disease. Inflamm Res 2005;54: 31–6.

350

M. Daheshia/Clin. Applied Immunol. Rev. 5 (2005) 339–351

[31] Kim S, Nadel JA. Role of neutrophils in mucus hypersecretion in COPD and implications for therapy. Treat Respir Med 2004;3(3):147–59. [32] Puljic R, Pahl A. Smoke induced changes in epithelial cell gene expression: development of an in vitro model for COPD. ALTEX 2004;21(1):3–7. [33] Beisswenger C, Platz J, Seifart C, Vogelmeier C, Bals R. Exposure of differentiated airway epithelial cells to volatile smoke in vitro. Respiration 2004;71(4):402–9. [34] Fuke S, Betsuyaku T, Nasuhara Y, Morikawa T, Katoh H, Nishimura M. Chemokines in bronchiolar epithelium in the development of chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2004;31(4): 405–12. [35] Saetta M, Baraldo S, Corbino L, Turato G, Braccioni F, Rea F, et al. CD8Cve cells in the lungs of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999 Aug;160(2):711–7. [36] Saetta M, Baraldo S, Turato G, Beghe B, Casoni GL, Bellettato CM, et al. Increased proportion of CD8C T-lymphocytes in the paratracheal lymph nodes of smokers with mild COPD. Sarcoidosis Vase Diffuse Lung Dis 2003;20(1):28–32. [37] Grumelli S, Cony DB, Song LZ, Song L, Green L, Huh J, et al. An immune basis for lung parenchymal destruction in chronic obstructive pulmonary disease and emphysema. PLoS Med 2004;1(1):e8. [38] Saetta M, Turato G, Maestrelli P, Mapp CE, Fabbri LM. Cellular and structural bases of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163(6):1304–9. [39] Miotto D, Ruggieri MP, Boschetto P, Cavallesco G, Papi A, Bononi I, et al. Interleukin-13 and -4 expression in the central airways of smokers with chronic bronchitis. Eur Respir J 2003;22(4):602–8. [40] Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest 2000;117(5 Suppl. 2): 398S–401S. [41] Sethi S, Evans N, Grant BJ, Murphy TF. New strains of bacteria and exacerbations of chronic obstructive pulmonary disease. N Engl J Med 2002;347(7):465–71. [42] Rohde G, Wiethege A, Borg I, Kauth M, Bauer TT, Gillissen A, et al. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease requiring hospitalisation: a case-control study. Thorax 2003;58(1): 37–42. [43] Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, Dejsomritrutai W, Charoenratanakul S. Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study. Chest 2004 Jun;125(6):2011–20. [44] Sethi S. New developments in the pathogenesis of acute exacerbations of chronic obstructive pulmonary disease. Curr Opin Infect Dis 2004;17(2):113–9. [45] Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J 2004;23(5):698–702. [46] Saetta M, Di Stefano A, Maestrelli P, Turato G, Ruggieri MP, Roggeri A, et al. Airway eosinophilia in chronic bronchitis during exacerbations. Am J Respir Crit Care Med 1994 Dec;150(6 Pt 1):1646–52. [47] Saetta M, Di Stefano A, Maestrelli P, Turato G, Mapp CE, Pieno M, et al. Airway eosinophilia and expression of interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin Exp Allergy 1996; 26(7):766–74. [48] Zhu J, Majumdar S, Qiu Y, Ansari T, Oliva A, Kips JC, et al. Interleukin-4 and interleukin-5 gene expression and inflammation in the mucus-secreting glands and subepithelial tissue of smokers with chronic bronchitis. Lack of relationship with CD8(C) cells. Am J Respir Crit Care Med 2001 Dec;164(12):2220–8. [49] DeMeo DL, Silverman EK. Alpha1-antitrypsin deficiency. 2: Genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 2004;59(3):259–64. [50] Celedon JC, Lange C, Raby BA, Litonjua AA, Palmer LJ, DeMeo DL, et al. The transforming growth factor-beta1(TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum Mol Genet 2004 Aug 1;13(15):1649–56. [51] Joos L. COPD and geneticsdwhat’s new? Swiss Med Wkly 2004;134(31–32):437–9. [52] Xu X, Rijcken B, Schouten JP, Weiss ST. Airways responsiveness and development and remission of chronic respiratory symptoms in adults. Lancet 1997;350(9089):1431–4.

M. Daheshia/Clin. Applied Immunol. Rev. 5 (2005) 339–351

351

[53] Silva GE, Sherrill DL, Guerra S, Barbee RA. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004;126(1):59–65. [54] Orie NG. Correlations of emphysema and asthmatic constitution. Acta Allergol 1961;16:407–9. [55] Gotfried MH. Macrolides for the treatment of chronic sinusitis, asthma, and COPD. Chest 2004 Feb;125 (2 Suppl):52S–60S. [56] Fabbri LM, Romagnoli M, Corbetta L, Casoni G, Busljetic K, Turato G, et al. Differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003 Feb 1;167(3):418–24. [57] Kay AB. T cells, cytokines and asthma. J R Coll Physicians Lond 1994;28(4):325–31. [58] Albers M, Schermer T, van den Boom G, Akkermans R, van Schayck C, van Herwaarden C, et al. Efficacy of inhaled steroids in undiagnosed subjects at high risk for COPD: results of the detection, intervention, and monitoring of COPD and asthma program. Chest 2004 Dec;126(6):1815–24. [59] Spira A, Beane J, Shah V, Liu G, Schembri F, Yang X, et al. Effects of cigarette smoke on the human airway epithelial cell transcriptome. Proc Natl Acad Sci U S A 2004;101(27):10143–8. [60] Ito K, Ito M, Elliott WM, Cosio B, Caramori G, Kon OM, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 2005;352(19):1967–76.