Pathogenesis of 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.
Inflammatory cellsCOPD 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.
Inflammatory mediatorsMany inflammatory mediators are increased in COPD,
including
x Leucotriene B4, a neutrophil and T cell chemoattractant which
is produced by macrophages, neutrophils, and epithelial cells
x Chemotactic factors such as the CXC chemokines interleukin
8 and growth related oncogene
, which are produced by
macrophages and epithelial cells. These attract cells from the
circulation and amplify pro-inflammatory responses
x Pro-inflammatory cytokines such as tumour necrosis factor

and interleukins 1 and 6
x Growth factors such as transforming growth factor , which
may cause fibrosis in the airways either directly or through
release of another cytokine, connective tissue growth factor.
Protease and antiprotease imbalanceIncreased 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
1 antitrypsin, secretory leucoprotease inhibitor, and
tissue inhibitors of metalloproteases.
Oxidative stressThe 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 B) and
hence gene expression of pro-inflammatory mediators.