Cellular and Molecular Mechanisms of Chronic Obstructive Pulmonary Disease

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Key points

  • Chronic inflammation in peripheral airways and lung parenchyma in patients with chronic obstructive pulmonary disease (COPD) may underlie progressive airways obstruction, may flare up during infective exacerbations, and extend into the systemic circulation to contribute to comorbidities.

  • Several cells are involved in COPD inflammation, including macrophages, epithelial cells, dendritic cells, neutrophils, eosinophils, and T and B lymphocytes.

  • These inflammatory and structural cells release many

Pathology

The progressive airflow limitation in COPD is caused by 2 major pathologic processes: remodeling and narrowing of small airways and destruction of the lung parenchyma with consequent destruction of the alveolar attachments of these airways as a result of emphysema. These pathologic changes are caused by chronic inflammation in the lung periphery, which increases as the disease progresses.4 Even in mild disease there is obstruction and loss of small airways.5 Analysis of serial computed

COPD as an inflammatory disease

There is a characteristic pattern of inflammation with increased numbers of macrophages, T lymphocytes, and B lymphocytes, together with increased numbers of neutrophils in the lumen.7, 8, 9 The inflammatory response in COPD involves both innate and adaptive immune responses, which are linked through the activation of dendritic cells.10 Multiple inflammatory mediators derived from inflammatory cells and structural cells of the airways and lungs are increased in COPD.11 A similar pattern of

Inflammatory cells

The inflammation of COPD lungs involves both innate immunity (neutrophils, macrophages, eosinophils, mast cells, natural killer cells, gamma delta T cells, and dendritic cells) and adaptive immunity (T and B lymphocytes) but also involves the activation of structural cells, including airway and alveolar epithelial cells, endothelial cells, and fibroblasts.

Epithelial cells

Epithelial cells are activated by cigarette smoke and other inhaled irritants, such as biomass fuel smoke, to produce inflammatory mediators, including tumor necrosis factor (TNF) alpha, interleukin (IL)-1 beta, IL-6, granulocyte-macrophage colony–stimulating factor (GM-CSF), and CXCL8 (IL-8). Epithelial cells in small airways may also be an important source of transforming growth factor (TGF) beta which then induces local fibrosis. Vascular endothelial growth factor (VEGF) seems to be

Macrophages

Macrophages play a key role in the pathophysiology of COPD and may orchestrate the chronic inflammatory response (Fig. 1).16 There is a marked increase (5-fold to 10-fold) in the numbers of macrophages in airways, lung parenchyma, bronchoalveolar lavage (BAL) fluid, and sputum in patients with COPD. Macrophages are localized to sites of alveolar wall destruction in patients with emphysema and there is a correlation between macrophage numbers in the parenchyma and severity of emphysema.17

Neutrophils

Increased numbers of activated neutrophils are found in sputum and BAL fluid of patients with COPD,33 although few neutrophils are seen airway wall and lung parenchyma, likely reflecting their rapid transit through these tissues. Neutrophil numbers in induced sputum correlate with COPD disease severity.33 Smoking has a direct stimulatory effect on granulocyte production and release from the bone marrow and survival in the respiratory tract, possibly mediated by GM-CSF and granulocyte

Eosinophils

Although eosinophils are the predominant leukocyte in asthma, their role in COPD is less certain. Increased numbers of eosinophils have been described in the airways and BAL of patients with stable COPD, whereas other investigators have not found increased numbers in airway biopsies, BAL, or induced sputum.39 The presence of eosinophils in patients with COPD predicts a response to corticosteroids and may indicate coexisting asthma.40, 41 Increased numbers of eosinophils have been reported in

Dendritic cells

Dendritic cell plays a central role in the linking of the innate to the adaptive immune response. The airways and lungs contain a rich network of dendritic cells that are localized near the surface, so that they are ideally located to signal the entry of foreign substances that are inhaled. Dendritic cells can activate a variety of other inflammatory and immune cells, including macrophages, neutrophils, and T and B lymphocytes, so dendritic cells may play an important role in the pulmonary

T lymphocytes

There is an increase in the total numbers of T lymphocytes in lung parenchyma, peripheral airways, and central airways of patients with COPD, with the greater increase in CD8+ than CD4+ cells.4, 23 There is a correlation between the numbers of T cells and the amount of alveolar destruction and the severity of airflow obstruction. Furthermore, the only significant difference in the inflammatory cell infiltrate in asymptomatic smokers and smokers with COPD is an increase in T cells, mainly CD8+

Mediators of inflammation

Many inflammatory mediators have now been implicated in COPD, including lipids, free radicals, cytokines, chemokines, and growth factors.11 These mediators are derived from inflammatory and structural cells in the lung and interact with each other in a complex manner. Because so many mediators are involved, it is unlikely that blocking a single mediator will have much clinical impact. Similar mediators in the lungs of patients with COPD may also be increased in the circulation and this systemic

Proteases

The increase in elastase activity in patients with COPD may contribute to the development of emphysema and to neutrophilic inflammation through the generation of chemotactic peptides such as Pro-Gly-Pro (matrikines). Human neutrophil elastase not only has elastolytic activity but is also a potent stimulant of mucus secretion in the airways. MMP9 seems to be the predominant elastolytic enzyme in COPD and is secreted from macrophages, neutrophils, and epithelial cells. MMP9 causes elastolysis but

Oxidative stress

Oxidative stress occurs when ROS are produced in excess of the antioxidant defense mechanisms and result in harmful effects, including damage to lipids, proteins, and DNA. Oxidative stress is a critical feature in COPD.67 Inflammatory and structural cells, including neutrophils, macrophages, and epithelial cells that are activated in the airways of patients with COPD, produce ROS. Superoxide anions (O2) are generated by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase and

Systemic inflammation in COPD

Patients with COPD, particularly when the disease is severe and during exacerbations, have evidence of systemic inflammation, measured either as increased circulating cytokines, chemokines, and acute phase proteins, or as abnormalities in circulating cells (Fig. 3).79, 80 Smoking may cause systemic inflammation (for example, increased total leukocyte count) but in patients with COPD the degree of systemic inflammation is greater. It is still uncertain whether these systemic markers of

Defective resolution of inflammation and repair

The reason why inflammation persists in patients with COPD even after long-term smoking cessation is currently unknown, but if the molecular and cellular mechanisms for impaired resolution could be identified this may provide a novel approach to COPD therapy. A major mechanism of airway obstruction in COPD is loss of elastic recoil caused by proteolytic destruction of lung parenchyma, so it is unlikely that this could be reversible by drug therapy. However, it might be possible to reduce the

Implications for future therapy

Inflammation is a driving mechanism for the progression of COPD, exacerbations, and probably associated comorbidities, including cardiovascular disease and lung cancer, which are the major causes of death among patients with COPD. However, this inflammatory process is largely resistant to the antiinflammatory effects of corticosteroids, although they are still widely used in the management of COPD, resulting in significant morbidity from side effects.

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