Pathology, pathogenesis, and pathophysiologyBMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7551.1202 (Published 18 May 2006) Cite this as: BMJ 2006;332:1202
- William MacNee, professor of respiratory and environmental medicine
- ELEGI, Colt Research, MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh.
Chronic obstructive pulmonary disease (COPD) is characterised by poorly reversible airflow obstruction and an abnormal inflammatory response in the lungs. The latter represents the innate and adaptive immune responses to long term exposure to noxious particles and gases, particularly cigarette smoke. All cigarette smokers have some inflammation in their lungs, but those who develop COPD have an enhanced or abnormal response to inhaling toxic agents. This amplified response may result in mucous hypersecretion (chronic bronchitis), tissue destruction (emphysema), and disruption of normal repair and defence mechanisms causing small airway inflammation and fibrosis (bronchiolitis).
These pathological changes result in increased resistance to airflow in the small conducting airways, increased compliance of the lungs, air trapping, and progressive airflow obstruction—all characteristic features of COPD. We have good understanding of the cellular and molecular mechanisms underlying the pathological changes found in COPD.
Inflammation is present in the lungs, particularly the small airways, of all people who smoke. This normal protective response to the inhaled toxins is amplified in COPD, leading to tissue destruction, impairment of the defence mechanisms that limit such destruction, and disruption of the repair mechanisms. In general, the inflammatory and structural changes in the airways increase with disease severity and persist even after smoking cessation. Besides inflammation, two other processes are involved in the pathogenesis of COPD—an imbalance between proteases and antiproteases and an imbalance between oxidants and antioxidants (oxidative stress) in the lungs.
This is the second in a series of 12 articles
COPD is characterised by increased numbers of neutrophils, macrophages, and T lymphocytes (CD8 more than CD4) in the lungs. In general, the extent of the inflammation is related to the degree of the airflow obstruction. These inflammatory cells release a variety of cytokines and mediators that participate in the disease process. This inflammatory pattern is markedly different from that seen in patients with asthma.
Many inflammatory mediators are increased in COPD, including
Leucotriene B4, a neutrophil and T cell chemoattractant which is produced by macrophages, neutrophils, and epithelial cells
Chemotactic factors such as the CXC chemokines interleukin 8 and growth related oncogene α, which are produced by macrophages and epithelial cells. These attract cells from the circulation and amplify pro-inflammatory responses
Pro-inflammatory cytokines such as tumour necrosis factor α and interleukins 1β and 6
Growth factors such as transforming growth factor β, which may cause fibrosis in the airways either directly or through release of another cytokine, connective tissue growth factor.
Protease and antiprotease imbalance
Increased production (or activity) of proteases and inactivation (or reduced production) of antiproteases results in imbalance. Cigarette smoke, and inflammation itself, produce oxidative stress, which primes several inflammatory cells to release a combination of proteases and inactivates several antiproteases by oxidation. The main proteases involved are those produced by neutrophils (including the serine proteases elastase, cathepsin G, and protease 3) and macrophages (cysteine proteases and cathepsins E, A, L, and S), and various matrix metalloproteases (MMP-8, MMP-9, and MMP-12). The main antiproteases involved in the pathogenesis of emphysema include α1 antitrypsin, secretory leucoprotease inhibitor, and tissue inhibitors of metalloproteases.
The oxidative burden is increased in COPD. Sources of oxidants include cigarette smoke and reactive oxygen and nitrogen species released from inflammatory cells. This creates an imbalance in oxidants and antioxidants of oxidative stress. Many markers of oxidative stress are increased in stable COPD and are further increased in exacerbations. Oxidative stress can lead to inactivation of antiproteases or stimulation of mucous production. It can also amplify inflammation by enhancing transcription factor activation (such as nuclear factor κB) and hence gene expression of pro-inflammatory mediators.
The above pathogenic mechanisms result in the pathological changes found in COPD. These in turn result in physiological abnormalities—mucous hypersecretion and ciliary dysfunction, airflow obstruction and hyperinflation, gas exchange abnormalities, pulmonary hypertension, and systemic effects.
Mucous hypersecretion and ciliary dysfunction
Mucous hypersecretion results in a chronic productive cough. This is characteristic of chronic bronchitis but not necessarily associated with airflow obstruction, and not all patients with COPD have symptomatic mucous hypersecretion. The hypersecretion is due to squamous metaplasia, increased numbers of goblet cells, and increased size of bronchial submucosal glands in response to chronic irritation by noxious particles and gases. Ciliary dysfunction is due to squamous metaplasia of epithelial cells and results in an abnormal mucociliary escalator and difficulty in expectorating.
Airflow obstruction and hyperinflation or air trapping
The main site of airflow obstruction occurs in the small conducting airways that are < 2 mm in diameter. This is because of inflammation and narrowing (airway remodelling) and inflammatory exudates in the small airways. Other factors contributing to airflow obstruction include loss of the lung elastic recoil (due to destruction of alveolar walls) and destruction of alveolar support (from alveolar attachments).
The airway obstruction progressively traps air during expiration, resulting in hyperinflation at rest and dynamic hyperinflation during exercise. Hyperinflation reduces the inspiratory capacity and therefore the functional residual capacity during exercise. These features result in breathlessness and limited exercise capacity typical of COPD. The airflow obstruction in COPD is best measured by spirometry and is a prerequisite for its diagnosis.
Gas exchange abnormalities
These occur in advanced disease and are characterised by arterial hypoxaemia with or without hypercapnia. An abnormal distribution of ventilation:perfusion ratios—due to the anatomical changes found in COPD—is the main mechanism for abnormal gas exchange. The extent of impairment of diffusing capacity for carbon monoxide per litre of alveolar volume correlates well with the severity of emphysema.
This develops late in COPD, at the time of severe gas exchange abnormalities. Contributing factors include pulmonary arterial constriction (as a result of hypoxia), endothelial dysfunction, remodelling of the pulmonary arteries (smooth muscle hypertrophy and hyperplasia), and destruction of the pulmonary capillary bed. Structural changes in the pulmonary arterioles result in persistent pulmonary hypertension and right ventricular hypertrophy or enlargement and dysfunction (cor pulmonale).
Systemic effects of COPD
Systemic inflammation and skeletal muscle wasting contribute to limiting the exercise capacity of patients and worsen the prognosis irrespective of degree of airflow obstruction. Patients also have an increased risk of cardiovascular disease, which is associated with an increase in C reactive protein.
Pathophysiology of exacerbations
Exacerbations are often associated with increased neutrophilic inflammation and, in some mild exacerbations, increased numbers of eosinophils. Exacerbations can be caused by infection (bacterial or viral), air pollution, and changes in ambient temperature.
In mild exacerbations, airflow obstruction is unchanged or only slightly increased. Severe exacerbations are associated with worsening of pulmonary gas exchange due to increased inequality between ventilation and perfusion and subsequent respiratory muscle fatigue. The worsening ventilation-perfusion relation results from airway inflammation, oedema, mucous hypersecretion, and bronchoconstriction. These reduce ventilation and cause hypoxic vasoconstriction of pulmonary arterioles, which in turn impairs perfusion.
Respiratory muscle fatigue and alveolar hypoventilation can contribute to hypoxaemia, hypercapnia, and respiratory acidosis, and lead to severe respiratory failure and death. Hypoxia and respiratory acidosis can induce pulmonary vasoconstriction, which increases the load on the right ventricle and, together with renal and hormonal changes, results in peripheral oedema.
The ABC of chronic obstructive pulmonary disease is edited by Graeme P Currie, specialist registrar, Respiratory Unit, Aberdeen Royal Infirmary, Aberdeen. The series will be published as a book by Blackwell Publishing in autumn 2006.
Competing interests GPC has received funding for attending international conferences and honoraria for giving talks from pharmaceutical companies GlaxoSmithKline, Pfizer, and AstraZeneca.
The pictures of a mid-saggital slice of lung removed from a patient with COPD and of the early changes of centrilobular emphysema and of panacinar emphysema are reproduced with permission from Hogg JC. Lancet 2004;364: 709-21. The pictures of normal small airway and of emphysematous airway are reproduced with permission from W MacNee and D Lamb.