Pathophysiology of COPD

Learning Objectives

This module will provide you with a brief overview of the pathophysiology of COPD.

By the end of this module you will be able to:

 Explain the difference between healthy lungs and lungs with COPD
 Describe the changes that occur in the lungs due to emphysema
 Describe the symptoms that are characteristic of chronic bronchitis
 Identify other respiratory conditions that may be confused with COPD
 Recognise the links between other chronic conditions and COPD.

What is COPD?

Chronic Obstructive Pulmonary Disease (COPD) is an umbrella term for a group of obstructive airway
disorders including chronic bronchitis, emphysema, small airways disease and chronic asthma (1).

COPD is defined as a disease which is mainly preventable and treatable, and associated with
significant extra-pulmonary consequences that may contribute to severity or outcomes (1). The
pulmonary component of COPD is characterised by airflow limitation that is not fully reversible. The
airflow limitation is usually progressive with an abnormal inflammatory response of the lungs to
noxious particles (2). In Australia this is mainly caused by cigarette smoking (1). In COPD the airflow
limitation is not fully or substantially reversible and is due to a combination of airway and
parenchymal damage. (Roll over to define parenchymal: Parenchymal refers to the functional tissue
of the lung (alveoli, alveolar ducts and bronchioles) as distinguished from connective or support
tissue.)

Clinical features

The clinical features and pathophysiology of COPD can overlap with chronic bronchitis, emphysema
and asthma. The inter-relationship of these conditions with airflow obstruction and COPD can be
illustrated by this Venn diagram (3).

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Reprinted with permission of the American Thoracic Society, copyright © 1995.

Spirometry testing will assist in differentiating asthma from COPD. Results that are fully reversible
after the administration of a bronchodilator are indicative of asthma and in this circumstance should
be treated as asthma and not COPD. There are similarities in the signs, symptoms and physiology
between asthma and COPD (1).

Patients with small airways disease, bronchiectasis and interstitial lung disease may also present with
similar symptoms to patients with COPD, sometimes with partially reversible airflow limitation (1).

Inflammation in COPD

COPD is a complex disease with many inflammatory pathways that initiate and potentiate the
disease process (4).

In Australia, smoking is the major cause of the inflammatory process leading to COPD. Passive
smoking in childhood, indoor air pollution, genetic factors, such as alpha 1 antitrypsin deficiency, and
chronic asthma can also cause the disease.

Figure reproduced with permission from COPDforum (4) (1)

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Neutrophils, macrophages and CD8+ T-lymphocytes are the key inflammatory cell types involved in
COPD (1) (4) (5) (6).

Airway inflammation in COPD is characterized by a neutrophilic inflammation with increased

numbers of macrophages and CD8+ T-lymphocytes. These cells release chemokines, cytokines and
proteases that are instrumental in producing a chronic inflammatory state (1) (4) (6) (5).

Bronchoconstriction in COPD

The autonomic nervous system regulates the contraction and relaxation of smooth muscle thus
controlling the diameter of the bronchioles, the rate of breathing and regulating the rate of airflow.

The autonomic nervous system is further divided into the sympathetic nervous system and
parasympathetic nervous system (as well as the enteric nervous system). In the respiratory system,
the sympathetic and parasympathetic systems have opposing actions.

Stimulation of the sympathetic nervous system (SNS) causes the smooth muscle of the bronchi and
bronchioles to relax, causing bronchodilation, whereas stimulation of the parasympathetic nervous
system (PNS) causes smooth muscle to contact, leading to bronchoconstriction (7).

Impaired lung function in COPD is caused by structural narrowing of the airways combined with the
effects of cholinergic vagal bronchoconstrictive tone and decreased elastic recoil (8).

Bronchodilators improve the airflow limitation observed in patients with COPD by producing airway
smooth muscle relaxation, although beta₂-agonists and anticholinergics achieve this effect through
different mechanisms (9).

a) Sympathetic nervous system b) Parasympathetic nervous system

Figure reproduced with permission from Boehringer Ingelheim Australia.

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The following are images of small airway obstructions (10).

Normal Mucus Plug

Reprinted from The Lancet, Vol 364, Hogg JC, Pathophysiology of airflow limitation in chronic obstructive pulmonary disease, 709-721,
copyright © 2004 with permission from Elsevier Ltd.

(A) Normal small airway.

(B) Small airway containing plug of mucus with relatively few cells, which could have been produced
in the glands of the larger airways and aspirated into the smaller airways.
(C) Inflamed airway with thickened wall in which the lumen is partly filled with an inflammatory
exudate of mucus and cells, which has probably been produced in the small airway.
(D) Airway surrounded by connective tissue, which appears as if it might restrict normal enlargement
of the lumen and unfolding of the epithelial lining that occurs with lung inflation.
(10)

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Airflow limitation and air trapping

One consequence of chronic airflow obstruction in COPD is air trapping and subsequent
hyperinflation.

Normal Hyperinflation

(11)

The x-rays show normal lungs and lungs that are hyper-inflated.

Posteroanterior chest radiograph findings consistent with COPD and hyperinflation may include:

• hyperlucency, indicated by the top arrow (hyperlucency on x-ray refers to less

density compared to a normal lung)

• a low-set or flat diaphragm, indicated by the bottom arrows

• a long, narrow heart shadow, indicated by the circle

• a widened or barrel-shaped chest.

This patient is unable to exhale all the air from their lungs. The trapped air generates an internal
pressure in the lungs, which makes it difficult for patients with COPD to breathe in. The air left
behind in the lungs takes up space in the thoracic cavity and pushes the diaphragm down. This
reduces efficiency of the diaphragm in its function as an inspiratory muscle. Patients with advanced
COPD can be very breathless due to the difficulty with inspiration as a result of this hyperinflation.

Emphysema

In emphysema the alveoli are damaged resulting in a significantly

reduced surface area for gas exchange to occur (12).

In the aveoli, macrophages and neutrophils try to phagocytose

toxic particles (such as smoke particles) to prevent them causing
damage. The neutrophils are, however, killed off in this process
leading to a series of events in which proteolytic enzymes (e.g.
elastase) are released. These enzymes destroy the walls of the
airsacs, which break down into larger air spaces, resulting in the
destruction of the lung parenchyma and the formation of a

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“bulla”. These bullae are less efficient in gas exchange than normal lung. The lungs are normally
protected against proteolytic enzymes by alpha-1-antiprotease, but toxins such as tobacco smoke
can destroy this protein causing a loss of this normal defence process.

The loss of elasticity in the lung parenchyma due to the destruction of elastin by the proteolytic
enzymes also causes airway collapse contributing to air trapping and hyperinflation of the lungs
which may clinically manifest as a “barrel chest”.

The combination of the mismatch between the blood flow and the airflow to the damaged aveoli
affects gas exchange. This compromises the performance of the respiratory pump, mainly the
respiratory muscles, due to the over-inflation and airway narrowing. This results in hypoventilation
and the feeling of breathlessness.

Chronic bronchitis

In chronic bronchitis there is persistent inflammation and

irritation of the bronchi and bronchioles, and increased mucus
production (12).

Chronic bronchitis is diagnosed if a patient experiences signs and

symptoms for 2 consecutive years. These signs and symptoms are
sputum production on most days for 3 months (12). Other
symptoms of chronic bronchitis may include wheezing and/or
shortness of breath.

Airway obstruction occurs in chronic bronchitis due to chronic

inflammation of the airway mucosa causing airway narrowing of
the airways. Airways constriction is a result of swelling and
excessive mucus production and/or increased vagal tone.

Frequent infections occur due to impaired clearance of secretions by the airway cilia (fine “hairs” on
the luminal surface of larger bronchi which are damaged by toxic stimuli such as cigarette smoke)
and altered function of the lung macrophages. Macrophages are inflammatory cells that play an
important role in destroying foreign particles, including bacteria.

Asthma

Asthma is a chronic inflammatory condition of the airways. Eosinophils are the predominant cell in
the inflammatory process (13).

Exposure to triggers results in increased inflammation, excessive mucus hypersecretion and

bronchoconstriction. These changes produce airway obstruction, chest tightness, breathlessness,
coughing and wheezing. Acute exacerbations can be rapid or gradual in onset, and may be severe
and potentially life threatening (13). Asthma (both in the steady state and during exacerbations) is
usually responsive to medicines that relax bronchial wall smooth muscle and/or reduce/control the
inflammation.
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COPD is commonly confused with or co-exists with asthma. This will be discussed in more detail later
in the training.

The following table provides a summary of the signs, symptoms and pathophysiology of the
conditions included in COPD.

Signs, Symptoms, Chronic Chronic

Pathophysiology Emphysema Bronchitis Asthma
Shortness of Breath √ √ √
Chronic Cough √
Excessive Mucus Production √
Frequent infections √
Alveolar destruction √
Airway narrowing √ √ √
Air trapping and
hyperinflation √ √ √
Loss of elasticity √
Inflammation and swelling
of airways √ √

Other Respiratory Conditions

In addition to asthma, other lung conditions that may co-exist with COPD are bronchiectasis and
interstitial lung disease (14).

Several studies have identified airflow obstruction as a risk factor for lung cancer, therefore patients
with COPD have a higher risk of developing lung cancer (15).

Bronchiectasis is a lung condition involving the permanent damage of the airways’ inner lining
causing dilation of the bronchi and bronchioles. It is usually accompanied by increased or excessive
sputum production. It is most often caused by a previous severe infection of the lungs such as
pneumonia in childhood, not by cigarette smoking (13).

Bronchiectasis may also be found in people with a range of immune deficiencies.

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Bronchiectasis is a chronic condition characterised by
repeated episodes of acute bronchial infection with increased
coughing and mucus production (13).

In bronchiectasis, sputum becomes difficult to clear. Sputum

can be trapped in “pockets” within the airways, which can
lead to further infections and damage to the airways (13).

The diagnosis is usually made by high resolution chest CT

scan.

The principal management strategies for bronchiectasis

include:

 Regular airway clearance to loosen and clear sputum (using positive end-expiratory pressure
devices and also huffing techniques)
 Vaccination against influenza and pneumococcal infection
 Avoiding known irritants (especially cigarette smoke)
 Using bronchodilator therapy and antibiotics (14)
 Pancreatic enzyme supplements if cystic fibrosis is present.

Interstitial Lung Diseases are a group of rare lung conditions that cause chronic breathlessness.
Generally the causes of these diseases are unknown (13).

There are many different types of interstitial lung disease and distinguishing them is often difficult.
Some disorders such as pulmonary fibrosis, only affects the lungs. Some medicines can trigger
pulmonary fibrosis, including amiodarone, nitrofurantoin, sulfasalazine and some cytotoxic agents
(e.g. bleomycin and methotrexate). (a full listing is provided by Bauman and Chan 2010) (16)

Other forms of interstitial lung disease occur as part of other conditions that affect other parts of the
body. For example, sarcoidosis and some of the other connective tissue disorders such as
rheumatoid arthritis and scleroderma (13).

Genetic factors may also play a role in a person developing COPD. Some families may be more
susceptible due to a lack of the protein alpha-1 antitrypsin (AAT). AAT is a protease inhibitor,
produced primarily in the liver, which protects the lungs and liver from the inflammatory enzyme
elastase. Elastase destroys elastin which maintains the elasticity of alveolar walls. With the resultant
loss of this elasticity, emphysema is likely to develop (17).

Normally AAT circulates in the blood and slows or stops the action of elastase. Cigarette smoke
directly inactivates AAT, so in the AAT deficient patient smoking is particularly harmful leading to an
increased risk of COPD and emphysema (17).

The prevalence of AAT Deficiency is estimated to affect approximately 1 in 2000 to 1 in 5000

individuals (18).

COPD – A multi-component disease

COPD is no longer considered a disease of the lung alone. It is recognized as a chronic, systemic
inflammatory syndrome that may involve other organs requiring independent diagnosis and
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treatment. Inflammation in the respiratory system may be accompanied by inflammation in the
cardiovascular, skeletal and nervous systems (19). These systemic consequences have a significant
impact on symptom burden, quality of life and outcomes. In addition to respiratory morbidities such
as lung cancer, increased risk of pneumonia, respiratory failure and end-stage lung disease, co-
morbidities include:

 Cardiovascular disease (coronary artery disease and chronic heart failure)

 Nutritional abnormalities and weight loss
 Hypoxaemia
 Skeletal muscle wasting
 Depression & anxiety
 Osteoporosis
 Diabetes
 Gastrointestinal disorders (notably gastro-oesophageal reflux disease)
 Worsening of other conditions such as anaemia.

This diagram is representative of the changes that occur in patients with COPD, which may all arise in
part from the inflammatory processes (19) (20).

Figure reproduced with permission from COPDforum (21)

As there is a high prevalence of co-morbid conditions in COPD, the assessment of this condition
needs to be multidimensional and include a screening for other complicating factors. Similarly it is
important to screen for COPD using spirometry in people with other conditions who complain of
breathlessness.

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 Look for

COPD Comorbidities

Look for
If Smoker

Figure reproduced with permission from COPDforum (21)

References

1. McKenzie, David K, et al., et al. The COPD-X Plan: Australian and New Zealand Guidelines for the
management of Chronic Obstructive Pulmonary Disease 2011. The COPD-X Plan: Australian and New
Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease 2011. [Online]
December 2011. [Cited: 3 August 2012.] http://www.copdx.org.au/home.

2. GOLD. Gobal strategy for the diagnosis, management, and prevention of chronic obstructive
pulmonary disease. Global Initiative for Chronic Obstructive Lung Disease. [Online] December 2011.
[Cited: 3 August 2012.] http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-
management.html.

3. American Thoracic Society. Standards for the diagnosis and care of patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med. 1995, Vol. 152, pp. 77-121.

4. COPDForum. Patterns of Inflammation. COPDForum. [Online] [Cited: 28 August 2012.]

http://copdforum.org/slib_engine/slib_frame.aspx.

5. Barnes, P J. Mechanisms in COPD. Differences from asthma. Chest. 2000, Vol. 117, Suppl 2, pp.
10S-14S.

6. Barnes, P J. COPD: is there light at the end of the tunnel? Curr Opin Pharmacol. 2004, Vol. 4, pp.
263-272.

7. Rang, H P, Dale, M M and Ritter, J M. Pharmacology. 3rd. s.l. : Churchill Livingstone, 1998. pp.
101-176.

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8. Barnes, P J. Managing Chronic Obstuctive Pulmonary Disease. 2nd. London:UK : Science Press Ltd.,
2001.

9. Tashkin, D P and Cooper, C B. The role of long-acting bronchodilators in the management of stable
COPD. Chest. 2004, Vol. 1, 125, pp. 249-259.

10. Hogg, James C. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease.
The Lancet. 21 August 2004, Vol. 364, pp. 709-721.

11. Hodder, R. COPD: Complex Obstructive Pulmonary Disease. Can J CME. Jan 2004.

12. Lung Foundation Australia. Lungs in Action Training, Session 4: COPD (Part I). 2009.

13. Lung Foundation Australia. Lungs in Action Training, Session 5: Other Respiratory Conditions.
2009.

14. Queensland Health and Lung Foundation Australia. Better Living with Chronic Obstructive
Pulmonary Disease: A Patient Guide. 2nd. Brisbane : Queensland Health and Lung Foundation
Australia, 2012. ISBN 978-0-9872272-0-1.

15. Maldonado, Fabien, et al., et al. Are airflow obstruction and radiographic evidence of
emphysema risk factors for lung cancer? Chest. 2010, Vol. 138, 6, pp. 1295-1302.

16. Bauman, K A and Chan, K M. Drug Induced Lung Disease. American College of Chest Physicians.
[Online] 15 04 2010. [Cited: 30 August 2012.] http://www.chestnet.org/accp/pccsu/drug-induced-
lung-disease?page=0,3.

17. Wood, A M and Stockley, R A. The genetics of COPD. Respiratory Research. 2006, Vol. 7, 130.

18. Stoller, J K and Aboussouan, L S. A review of α 1 antitrysin deficiency. Am J Respir Crit Care Med.
2012, Vol. 3, 185, pp. 246-59.

19. Agusti, A G, et al., et al. Systemic effects of chronic obstructive pulmonary disease. European
Respiratory Journal. 2003, Vol. 21, pp. 347-360.

20. Agusti, A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we
don't know (but should). Proceedings of the American Thoracic Society. 2007, Vol. 4, 7, pp. 522-525.

21. COPDforum. Systemic Inflammation and Comorbidities in COPD. COPDforum. [Online] [Cited: 1
October 2010.] http://copdforum.org/slide-library/copd-slides/systemic-inflammation-and-
comorbidities-in-copd.aspx.

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