Reviews and feature article
Inflammatory mechanisms in patients with chronic obstructive pulmonary disease

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Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation affecting predominantly the lung parenchyma and peripheral airways that results in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased numbers of alveolar macrophages, neutrophils, T lymphocytes (predominantly TC1, TH1, and TH17 cells), and innate lymphoid cells recruited from the circulation. These cells and structural cells, including epithelial and endothelial cells and fibroblasts, secrete a variety of proinflammatory mediators, including cytokines, chemokines, growth factors, and lipid mediators. Although most patients with COPD have a predominantly neutrophilic inflammation, some have an increase in eosinophil counts, which might be orchestrated by TH2 cells and type 2 innate lymphoid cells though release of IL-33 from epithelial cells. These patients might be more responsive to corticosteroids and bronchodilators. Oxidative stress plays a key role in driving COPD-related inflammation, even in ex-smokers, and might result in activation of the proinflammatory transcription factor nuclear factor κB (NF-κB), impaired antiprotease defenses, DNA damage, cellular senescence, autoantibody generation, and corticosteroid resistance though inactivation of histone deacetylase 2. Systemic inflammation is also found in patients with COPD and can worsen comorbidities, such as cardiovascular diseases, diabetes, and osteoporosis. Accelerated aging in the lungs of patients with COPD can also generate inflammatory protein release from senescent cells in the lung. In the future, it will be important to recognize phenotypes of patients with optimal responses to more specific therapies, and development of biomarkers that identify the therapeutic phenotypes will be important.

Section snippets

Pathology of COPD

The progressive airflow limitation in patients with COPD results from 2 major pathological processes: remodeling and narrowing of the small airways and destruction of the lung parenchyma with consequent loss of the alveolar attachments of these airways as a result of emphysema. These pathological changes appear to be the consequence of chronic inflammation in the lung periphery, the intensity of which increases as the disease progresses.9 Even in patients with mild disease, there is obstruction

Characteristics of COPD-related inflammation

In patients with COPD, there is a characteristic pattern of inflammation with increased numbers of neutrophils in the airway lumen and increased numbers of macrophages, T lymphocytes, and B lymphocytes.9, 16, 17 The inflammatory response in patients with COPD involves both innate and adaptive immune responses, which are linked through activation of dendritic cells.18 A similar pattern of inflammation and mediator expression is found in smokers without airflow limitation, but in patients with

Inflammatory cells

The inflammation seen in the lungs of patients with COPD involves both innate immunity (neutrophils, macrophages, eosinophils, mast cells, natural killer cells, γδ T cells, innate lymphoid cells, and dendritic cells) and adaptive immunity (T and B lymphocytes), but also, there is activation of structural cells, including airway and alveolar epithelial cells, endothelial cells, and fibroblasts.

Inflammatory mediators

Many inflammatory mediators have been implicated in COPD, including lipids, free radicals, cytokines, chemokines, and growth factors.80 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 a significant clinical effect. Similar mediators that are found in the lungs of patients with COPD might also be increased in the

Oxidative stress as a major driving mechanism

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 patients with COPD.95 Inflammatory and structural cells, including neutrophils, macrophages, and epithelial cells, which are activated in the airways of patients with COPD, produce ROS. Superoxide anions (O2.−) are generated by NADPH oxidase and converted to hydrogen peroxide (H2O2)

Systemic inflammation in patients with COPD

Patients with COPD, particularly when the disease is severe and during exacerbations, have evidence of systemic inflammation, which is measured either as increased circulating cytokine, chemokine, and acute-phase protein levels or as abnormalities in circulating cells.105, 106 Persistent inflammation is associated with poorer clinical outcomes. Smoking itself can cause systemic inflammation (eg, increased total leukocyte count), but in patients with COPD, the degree of systemic inflammation is

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 might provide a novel approach to COPD therapy. A major mechanism of airway obstruction in patients with COPD is loss of elastic recoil because of proteolytic destruction of lung parenchyma, and therefore it is unlikely that this could be reversible by drug therapy. However, it

Future implications

There is a need to identify phenotypes of COPD that respond to specific therapies, and this will involve recognizing disease endotypes and biomarkers that predict response.

As discussed above, some patients with COPD have eosinophilic inflammation, and this can be recognized by increased blood eosinophil numbers, which might indicate patients who have a better therapeutic response to inhaled corticosteroids. Prospective studies are needed to define the cutoff point for blood eosinophils that

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    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, and William T. Shearer, MD PhD

    Disclosure of potential conflict of interest: P. J. Barnes has served on Scientific Advisory Boards of AstraZeneca, Boehringer-Ingelheim, Chiesi, GlaxoSmithKline, Glenmark, Johnson & Johnson, Merck, Novartis, Takeda, Pfizer, RespiVert, Sun Pharmaceuticals, and Teva; and has received research funding from AstraZeneca, Boehringer-Ingelheim, Chiesi, Heptares, Novartis, Takeda, and Pfizer.

    Terms in boldface and italics are defined in the glossary on page 17.

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