PATHOLOGY ONCOLOGY RESEARCH
Vol 12, No 1, 2006
Article is available online at http://www.webio.hu/por/2006/12/1/0052
SEMINAR Pathology of Chronic Obstructive Pulmonary Disease Mária SZILASI,1 Tamás DOLINAY, 1 Zoltán NEMES, 2 János STRAUSZ3 Departments of 1Pulmonary Medicine, and 2Pathology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary, 3”Korányi” National Institute for Tuberculosis and Pulmonology, Budapest, Hungary Chronic obstructive pulmonary disease is one of the leading causes of death and morbidity worldwide. Despite intensive investigation, its pathology and pathophysiology are not well understood. The hallmarks of the disease are irreversible airflow limitation and chronic inflammation. Small airway obstruction due to progressive inflammation and fibrosis, and the loss of elastic recoil mediated by elastolysis and apoptosis equally contribute to pathologic changes. However, it is debated to what extent the obstruction of large airways leads to altered lung function. Three morphologic entities are described in the literature under one disease; chronic bronchitis, obstructive bronchiolitis and emphysema may appear in the same patient at the
same time. The authors review pathologic changes observed in chronic obstructive pulmonary disease, including acute exacerbations and secondary pulmonary hypertension as severe but common complications of the disease. Furthermore, we detail recent scientific evidences for major cellular and molecular inflammatory pathway activation. These mechanisms result in accelerated apoptosis, remodeling and increased proinflammatory cytokine release. Targeting intracellular pathological changes may lead to the discovery of a new generation of drugs that could reduce chronic obstruction before airway irreversibility is established. (Pathology Oncology Research Vol 12, No 1, 52–60)
Key words: chronic bronchitis, obstructive bronchiolitis, emphysema, inflammation
Introduction Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. At present, it is the 4th most common cause of death among adults, and it is estimated to rank 3rd by 2020.13 Because of its increasing incidence, the World Health Organization (WHO) and the US National Institute of Health experts formed the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), and described the Global Strategy for the Diagnosis, Management and Prevention of COPD. Their report was published in 2001 and updated in 2003. The importance of COPD need to be further emphasized in Central and Eastern Europe because of the high prevalence of smoking. According to WHO statistics, in this region the prevalence of COPD is also the Received: Nov 5, 2005; accepted: Jan 15, 2006 Correspondence: Mária SZILASI M.D., Department of Pulmonary Medicine, University of Debrecen Medical and Health Science Center, Móricz Zs. krt. 22., Debrecen, H-4004, Hungary. Phone/Fax: +36-52-414222, E-mail:
[email protected]
© 2006 Arányi Lajos Foundation
highest.35 Recent Hungarian statistics show that the prevalence of COPD is 609.27 cases/100,000, but due to the late diagnosis of the disease the real number is underestimated.2 COPD is calculated to affect 400,000-500,000 people in Hungary. Although considerable attention is paid to the prevention and treatment of the disease, the complex pathology and the progressive nature of COPD is not well understood. The GOLD definition describes COPD as “A disease state characterized by airflow limitation that is not fully reversible. The limitation is usually progressive and associated with and abnormal inflammatory response of the lungs to noxious particles or gases.” GOLD criteria use lung function parameters such as forced expiration volume in 1 s (FEV1) compared to predicted FEV1 and FEV1/FVC (forced vital capacity) to classify the severity of the disease. The most prominent pathological and pathophysiological changes seen in COPD are progressive airflow limitation and peripheral airway inflammation. Airflow limitation results from the loss of elastic recoil of the parenchyma and from the increase in airway resistance. In emphy-
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Table 1. Cellular and structural changes in the lung in chronic obstructive pulmonary disease Central airways wall Increase in macrophages and T lymphocytes (particularly CD8+ T lymphocytes). Neutrophils in severe disease Lumen
Neutrophils
Peripheral airways
Goblet cell metaplasia and mucous plugging Smooth muscle cell hypertrophy. Fibrosis. Inflammation (particularly CD8+ T lymphocytes). All inflammatory cells including neutrophils in severe disease
Parenchyma
Inflammation (particularly CD8+ T lymphocytes). Destruction (centriacinar and panacinar emphysema). Fibrosis
Pulmonary arteries
Endothelial dysfunction. Intima thickening Medial thickening (less frequently). Adventitial inflammation (particularly CD8+ T lymphocytes)
sematous lungs, parenchyma destruction and loss of alveolar integrity is observed, which lead to reduced recoil and collapsed small airway lumens. Inflammatory cell immigration to the small airways, together with fibrosis and smooth muscle cell proliferation results in reduced diameter and increased resistance. It is not yet clear whether mucus hypersecretion adds to airflow limitation.54 Mucus hypersecretion is typical in central airways in patients with chronic bronchitis. There is increasing evidence that larger airways are also involved in the inflammatory process in COPD.48 Despite similarities in altered lung function, clinical signs and symptoms of COPD manifest as different pathologic entities. Chronic bronchitis, emphysema and obstructive bronchiolitis are the three morphological forms of COPD, however, these diseases can be present in mixed forms in the same patient.18 Although it is somewhat artificial to separate these diseases, in this review we describe them separately to give more insight of the complexity of COPD. Furthermore, we would like to draw attention to the systemic consequences of severe COPD, including pulmonary hypertension and skeletal muscle wasting. Chronic bronchitis Chronic bronchitis is defined clinically by a productive cough lasting for at least 3 months, recurring in at least 2 consecutive years, if it cannot be attributed to other pulmonary or cardiac condition.33 Chronic bronchitis results from mucus hypersecretion, which does not always lead to airway obstruction. In pathology, chronic bronchitis also means certain microscopic and macroscopic changes in the airway structure, such as mucus production, epithelial changes, airway inflammation, smooth muscle cell hypertrophy and submucosal bronchial gland enlargement. Macroscopically, mucus overflow is observed that affects mainly the intermediate bronchi, 2-4 mm in diameter. Vol 12, No 1, 2006
Microscopically, mucus is present in lumen and goblet cell hyperplasia is observed in the bronchial wall. In chronic bronchitis, goblet cells expand to the bronchioli to the expense of ciliated epithelial cells, serous and Clara cells. In chronic bronchitis epithelial atrophy, squamous cell metaplasia and ciliar abnormalities were described in small bronchi. Despite these changes, the epithelium is intact and thickness of reticular basement membrane is in normal range. This is a key difference between asthma and chronic bronchitis/COPD pathology. Epithelial injury and thickening of the basal membrane is observed early on in asthma.38,40 Inflammation is observed in the mucosa, in the smooth muscle cell layers and submucosal glands. Inflammation is a better pathologic marker of chronic bronchitis than mucous gland hypertrophy. In large airways (>2 mm) mononuclear cell, macrophage, CD8+ T lymphocyte and plasma cell involvement was observed in stable COPD and during exacerbations of chronic bronchitis.49,50,52 The role of neutrophil leukocytes is not yet clear. Neutrophils are seen in the large airway walls only during exacerbations and in severe COPD. Neutrophils, however, are observed early on in the airway lumen and in the sputum.7 In small airways, CD8+ T lymphocyte-mediated inflammation is dominant, but in severe forms of the disease other inflammatory cells, including neutrophils infiltrate the airway walls. Cell involvement in COPD is shown in Table 1. CD8+ cytotoxic T lymphocytes infiltrate all levels of the bronchial tree in COPD. There are at least two theories for the CD4+/CD8+ ratio shift in the disease. First, CD8+ T cells frequently occur on site of viral infections. It is suggested that repeated viral infections lead to the excessive recruitment of lymphocytes. CD8+ cells release tumor necrosis factor-α, a potent proinflammatory mediator that leads to airway injury.30 Second, Enelow and colleagues demonstrated that lymphocytes are activated by lung autoantigens and cause lung injury.9 It is speculated that tobacco smoke can induce autoantigen response in the
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lung, which causes the increased presence of CD8+ T lymphocytes. The role of inflammatory cell mediators in progression of COPD is detailed below in “Inflammatory mediators in COPD”. Smooth muscle cell hypertrophy is often observed in chronic bronchitis, but it is difficult to assess due to the fact that some bronchi do not have a complete smooth muscle layer. Airway thickening is more prominent in obstructive bronchiolitis than in chronic bronchitis. Submucosal bronchial gland enlargement is a key feature in chronic bronchitis and it was described early on.44 The Reid index, which is a calculated ratio: submucosal gland layer thickness/total airway wall thickness (from epithelium base to inner cartilage surface) is greater than 0.5 (normal index is 0.3).43 Furthermore, the proportion of mucous glands in the acini is increased and that of serous ones is reduced. Serous glands produce lysozyme and lactoferrin that have antibacterial activity. The thick mucous plugs likely clotting airways and the reduced serous activity may contribute to common bacterial infections in COPD.13 The degeneration of bronchial cartilage appears in a late phase of chronic bronchitis.14 As mentioned above, mucus hypersecretion is a hallmark of chronic bronchitis (Figure 1). It is observed as chronic cough and sputum production in patients with chronic bronchitis. Mucus hypersecretion is a result of local peptidergic and spinal cholinergic sensory nerve activation. Besides mucus production it directly induces neutrophil elastase and chymase production. There is cumulating data that epidermal growth factor receptor (EGFR) plays a central role in mucus overproduction. It is suggested to be the final common pathway by which noxa, including tobacco smoke, causes mucus hyperplasia.45,60 EGF, together with other growth factors, may stimulate submucosal gland and goblet cell proliferation in chronic bron-
a
chitis. Tobacco smoke itself can activate the EGFR pathway and cause mucus hypersecretion.6 It is still debated whether mucus hypersecretion has a role in airway obstruction.54 Epidemiological data suggest that hypersecretion is a risk factor for obstruction, and mucus contributes to reduced airflow.64 Two large clinical trials, however, showed that the presence of chronic bronchitis does not predict the development of airflow limitation.10,63 Furthermore, in a recent analysis of 153 COPD patients’ bronchial biopsy data, Hogg and colleagues did not find correlation between the luminar content and the severity of small airway obstruction.15 Obstructive bronchiolitis Obstructive bronchiolitis is an inflammatory condition that involves small and peripheral airways (
