Reviews and feature articleInflammatory mechanisms in patients with chronic obstructive pulmonary disease
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
References (118)
- et al.
Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010
Lancet
(2012) Cellular and molecular mechanisms of chronic obstructive pulmonary disease
Clin Chest Med
(2014)- et al.
Chronic obstructive pulmonary disease: clinical integrative physiology
Clin Chest Med
(2014) - et al.
New insights into the immunology of chronic obstructive pulmonary disease
Lancet
(2011) - et al.
Simultaneous assessment of hepatocyte growth factor and vascular endothelial growth factor in epithelial lining fluid from patients with COPD
Chest
(2014) - et al.
Supplementing defect in Club Cell Secretory Protein attenuates airway inflammation in COPD
Chest
(2015) Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease
J Allergy Clin Immunol
(2013)- et al.
Defective phagocytosis in airways disease
Chest
(2012) - et al.
The asthma-COPD overlap syndrome: towards a revised taxonomy of chronic airways diseases?
Lancet Respir Med
(2015) Asthma-COPD Overlap
Chest
(2016)
Defining the asthma-COPD overlap syndrome in a COPD cohort
Chest
Type 2 innate lymphoid cells: new players in asthma and allergy
Curr Opin Immunol
Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials
Lancet Respir Med
CXCR3 and CCR5 chemokines in the induced sputum from patients with COPD
Chest
Antiendothelial cell antibodies in patients with COPD
Chest
Neutrophil chemotactic activity of sputum from patients with COPD: role of interleukin 8 and leukotriene B4
Chest
Canakinumab for the treatment of chronic obstructive pulmonary disease
Pulm Pharmacol Ther
Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD
Chest
Chemokine receptors as therapeutic targets in chronic obstructive pulmonary disease
Trends Pharmacol Sci
Oxidative stress in COPD
Chest
Peroxynitrite elevation in exhaled breath condensate of COPD and its inhibition by fudosteine
Chest
Decreased histone deacetylase 2 impairs Nrf2 activation by oxidative stress
Biochem Biophys Res Commun
Chronic obstructive pulmonary disease
Nat Rev Dis Primers
Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema
Thorax
Clinical COPD phenotypes: a novel approach using principal component and cluster analyses
Eur Respir J
Lung-function trajectories leading to chronic obstructive pulmonary disease
N Engl J Med
Physiological and inflammatory phenotypic comparisons between non-smoking and smoking COPD
Eur Resp J
New anti-inflammatory treatments for chronic obstructive pulmonary disease
Nat Rev Drug Discov
The nature of small-airway obstruction in chronic obstructive pulmonary disease
N Engl J Med
Small-airway obstruction and emphysema in chronic obstructive pulmonary disease
N Engl J Med
Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression
Nat Med
Mechanisms of dyspnea during cycle exercise in symptomatic patients with GOLD stage I chronic obstructive pulmonary disease
Am J Respir Crit Care Med
Respiratory health effects of indoor air pollution
Int J Tuberc Lung Dis
Marijuana and lung diseases
Curr Opin Pulm Med
Immunology of asthma and chronic obstructive pulmonary disease
Nat Immunol Rev
Dendritic cells in pathogenesis of COPD
Curr Pharm Des
Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis
Eur Respir J
Bronchial epithelial cells: The key effector cells in the pathogenesis of chronic obstructive pulmonary disease?
Respirology
Expression of epidermal growth factors and their receptors in the bronchial epithelium of subjects with chronic obstructive pulmonary disease
Am J Clin Pathol
Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis
Am J Respir Crit Care Med
Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium
Thorax
Cigarette smoke Induces MUC5AC mucin overproduction via tumor necrosis factor-a converting enzyme in human airway epithelial (NCI-H292) cells
Am J Physiol Lung Cell Mol Physiol
Epidermal growth factor receptor inhibitor AG1478 inhibits mucus hypersecretion in airway epithelium
Am J Rhinol Allergy
Safety and efficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary disease
Am J Respir Crit Care Med
Macrophages as orchestrators of COPD
COPD
Alveolar macrophage-mediated elastolysis: roles of matrix metalloproteinases, cysteine, and serine proteases
Am J Physiol Lung Cell Mol Physiol
Tissue macrophage heterogeneity: issues and prospects
Semin Immunopathol
Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease
J Allergy Clin Immunol
Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations
Thorax
Elevated levels of the chemokines GRO-a and MCP-1 in sputum samples from COPD patients
Thorax
Cited by (948)
Gut microbiota nexus: Exploring the interactions with the brain, heart, lungs, and skin axes and their effects on health
2024, Medicine in MicroecologyMusculoskeletal crosstalk in chronic obstructive pulmonary disease and comorbidities: Emerging roles and therapeutic potentials
2024, Pharmacology and TherapeuticsThe activation of the AIM2 inflammasome after cigarette smoke exposure leads to an immunosuppressive lung microenvironment
2024, International Immunopharmacology
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.