Global Initiative for Chronic Obstructive Lung Disease - GOLD

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GOLD_WR_05 8/18/05 12:56 PM Page 29 time, inflammation damages the lungs and leads to the pathologic changes characteristic of COPD. In addition to inflammation, two other processes thought to be important in the pathogenesis of COPD are an imbalance of proteinases and antiproteinases in the lung, and oxidative stress. These processes may themselves be consequences of inflammation, or they may arise from environmental (e.g., oxidant compounds in cigarette smoke) or genetic (e.g., alpha-1 antitrypsin deficiency) factors. Figure 4-1 details the interactions between these mechanisms. The multiplicity of cells and mediators thought to be involved in the pathogenesis of COPD is presented schematically in Figure 4-2. Inflammatory Cells COPD is characterized by an increase in neutrophils, macrophages, and T lymphocytes (especially CD8 + ) in various parts of the lung (Figure 4-3). There may also be an increase in eosinophils in some patients, particularly during exacerbations. These increases are brought about by increases in inflammatory cell recruitment, survival, and/or activation. Many studies reveal a correlation between the number of inflammatory cells of various types in the lung and the severity of COPD 1-10 . Figure 4-3. Sites of Inflammatory Cell Increases in COPD Anti-oxidants Figure 4-1. Pathogenesis of COPD Oxidative stress Noxious particles and gases Lung Inflammation Antiproteinases Proteinases Large Airways Small Airways Parenchyma • Macrophages • T lymphocytes (especially CD8 + ) • Neutrophils (severe disease only) • Eosinophils (in some patients) • Macrophages • T lymphocytes (especially CD8 + ) • Eosinophils (in some patients) • Macrophages • T lymphocytes (especially CD8 + ) • Neutrophils COPD pathology Repair mechanisms Pulmonary Arteries • T lymphocytes (especially CD8 + ) • Neutrophils Figure 4-2. Cells and Mediators Involved in the Pathogenesis of COPD CELLS Macrophages Neutrophils CD8 + lymphocytes Eosinophils Epithelial cells Fibroblasts Printed with permission of Dr. Peter J. Barnes. MEDIATORS LTB4 IL-8, GRO-1 MCP-1, MIP-1 GM-CSF 4 Endothelin Substance P -1 PROTEINASES Neutrophil elastase Cathepsins Proteinase-3 MMPs EFFECTS Mucus hypersecretion Fibrosis Alveolar wall destruction Neutrophils. Increased numbers of activated neutrophils are found in sputum and bronchoalveolar lavage (BAL) fluid of patients with COPD 4,5,8,9 , although the role of neutrophils in COPD is not yet clear. Neutrophils are also increased in smokers without COPD 11 . However, neutrophils are little increased in airway and parenchyma tissue sections, which may reflect their rapid transit through these parts of the lung. Induced sputum studies also show an increase in myeloperoxidase (MPO) and human neutrophil lipocalin, indicating neutrophil activation 12 . Exacerbations of COPD are characterized by a marked increase in the number of neutrophils in BAL fluid 13 . Neutrophils secrete several proteinases, including neutrophil elastase (NE), neutrophil cathepsin G, and neutrophil proteinase-3, which may contribute to parenchymal destruction and chronic mucus hypersecretion. Macrophages. Increased numbers of macrophages are present in the large and small airways and lung PATHOGENESIS, PATHOLOGY, AND PATHOPHYSIOLOGY 29
GOLD_WR_05 8/18/05 12:56 PM Page 30 parenchyma of patients with COPD, as reflected in histopathology, BAL, bronchial biopsy, and induced sputum studies 2,4-6,9 . In patients with emphysema, macrophages are localized to sites of alveolar wall destruction 1 . Macrophages likely play an orchestrating role in COPD inflammation by releasing mediators such as tumor necrosis factor- (TNF-), interleukin 8 (IL-8), and leukotriene B4 (LTB4), which promote neutrophilic inflammation. T lymphocytes. Histopathology and bronchial biopsy studies show an increase in T lymphocytes, especially CD8 + (cytotoxic) cells, throughout the lungs of patients with COPD 1,2,10,14 . Their role in COPD inflammation is not yet fully understood, but one way that CD8 + cells may contribute to COPD is by releasing perforin, granzyme-B, and TNF-, which can cause the cytolysis and apoptosis of alveolar epithelial cells 15 that may be responsible for the persistence of inflammation. An increased number of lymphocyte-like natural killer (NK) cells has also been reported in patients with severe COPD 3 . Eosinophils. The presence and role of eosinophils in COPD are uncertain. Some bronchial biopsy studies show eosinophils increased in the airways of some patients with stable COPD 6,16 . However, some of these patients may have had coexisting asthma, as other studies report no increase in eosinophils in COPD patients 2 . The levels of eosinophil cationic protein (ECP) and eosinophil peroxidase (EPO) in induced sputum are elevated in COPD, suggesting that eosinophils may be present but degranulated, and therefore no longer recognizable by light microscopy 12 . The high levels of neutrophil elastase (NE) often found in COPD may be responsible for this degranulation 17 . Most studies agree that airway eosinophils are increased during exacerbations of COPD 18,19 . Epithelial cells. Airway and alveolar epithelial cells are likely to be important sources of inflammatory mediators in COPD, though their role in inflammation in this disease has not yet been thoroughly studied. Exposure of nasal or bronchial epithelial cells from healthy volunteers to nitrogen dioxide (NO 2 ), ozone (O 3 ), and diesel exhaust particles results in significant synthesis and release of proinflammatory mediators, including eicosanoids, cytokines, and adhesion molecules 20 . The adhesion molecule E-selectin, involved in recruitment and adhesion of neutrophils, is up-regulated on airway epithelial cells in COPD patients 21 . Cultured human bronchial epithelial cells from COPD patients release lower levels of inflammatory mediators such as TNF- and IL-8 than similar preparations from nonsmokers or smokers without COPD, suggesting that some form of down-regulation of inflammatory mediator release may occur in epithelial cells of individuals with COPD 20 . Inflammatory Mediators Activated inflammatory cells in COPD release a variety of mediators, including a spectrum of potent proteinases 22,23 , oxidants 24 , and toxic peptides 25 . Many of the mediators thought to be important in the disease – notably LTB4 26 , IL-8 4,27 , and TNF- 4,16 – are capable of damaging lung structures and/or sustaining neutrophilic inflammation. The damage induced by these moieties may further potentiate inflammation by releasing chemotactic peptides from the extracellular matrix 28 . Little is yet known about the specific role of these inflammatory mediators in COPD. Studies of the therapeutic use of selective mediator antagonists should identify the molecules relevant in COPD. Leukotriene B4 (LTB4). LTB4, a potent chemoattractant of neutrophils, is found at increased levels in the sputum of patients with COPD 26 . It is probably derived from alveolar macrophages, which secrete more LTB4 in patients with COPD. Several potent LTB4 receptor antagonists have been developed for clinical studies and should elucidate further the role of this mediator in COPD. So far there is no evidence that cysteinyl leukotrienes (LTC4, LTD4, LTE4) are involved in COPD. Selective antagonists of the cysteinyl leukotriene 1 receptor (CysLT 1 ) have proven helpful in patients with asthma and studies of these drugs in COPD patients are now underway. The role of the cysteinyl leukotriene 2 receptor (CysLT 2 ) in respiratory disease is as yet unknown 29 . Interleukin 8 (IL-8). IL-8, a selective chemoattractant of neutrophils that may be secreted by macrophages, neutrophils, and airway epithelial cells, is present at high concentrations in induced sputum and BAL fluid of patients with COPD 4,27 . IL-8 may play a primary role in the activation of both neutrophils and eosinophils in the airways of COPD patients and may serve as a marker in evaluating the severity of airway inflammation 27 . Tumor necrosis factor- (TNF-). TNF- activates the transcription factor nuclear factor-B (NF-B), which in turn activates the IL-8 gene in epithelial cells and macrophages (Figure 4-4). TNF- is present at high concentrations in sputum 4 and is detectable in bronchial biopsies 16 in patients with COPD. TNF- serum levels and production by peripheral blood monocytes are increased in weight-losing COPD patients, suggesting that this mediator may play a role in the cachexia of severe COPD 30 . 30 PATHOGENESIS, PATHOLOGY, AND PATHOPHYSIOLOGY
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Global Initiative for Chronic Obstructive Lung Disease - GOLD

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