Inflammatory mechanisms in COPD.

Cigarette smoke (and other irritants) activate macrophages in the respiratory tract that
release neutrophil chemotactic factors, including IL-8 and LTB4. These cells then release
proteases that break down connective tissue in the lung parenchyma, resulting in
emphysema, and also stimulate mucus hypersecretion. These enzymes are normally
counteracted by protease inhibitors, including 1-antitrypsin, SLPI, and TIMP. Cytotoxic T cells
(CD8) may also be recruited and may be involved in alveolar wall destruction. Fibroblasts
may be activated by growth factors releases from macrophages and epithelial cells. CTG,
connective tissue growth factor; COB, chronic obstructive bronchiolitis.

COPD is characterized by airflow limitation that is poorly reversible. Cumulative, chronic

exposure to cigarette smoking is the number one cause of the disease, but repeated
exposure to secondhand smoke, air pollution and occupational exposure (to coal, cotton,
grain) are also important risk factors.
Chronic inflammation plays a major role in COPD pathophysiology. Smoking and other
airway irritants cause neutrophils, T-lymphocytes, and other inflammatory cells to
accumulate in the airways. Once activated, they trigger an inflammatory response in which
an influx of molecules, known as inflammatory mediators, navigate to the site in an attempt
to destroy and remove inhaled foreign debris.

Under normal circumstances, the inflammatory response is useful and leads to healing. In
fact, without it, the body would never recover from injury. In COPD, repeated exposure to
airway irritants perpetuates an ongoing inflammatory response that never seems to shut
itself off. Over time, this process causes structural and physiological lung changes that get
progressively worse.
As inflammation continues, the airways constrict, becoming excessively narrow and swollen.
This leads to excess mucus production and poorly functioning cilia, a combination that
makes airway clearance especially difficult. When people with COPD can't clear their
secretions, they develop the hallmark symptoms of COPD, including a chronic, productive
cough, wheezing and dyspnea. Finally, the build-up of mucus attracts a host of bacteria that
thrive and multiply in the warm, moist environment of the airway and lungs. The end result
is further inflammation, the formation of diverticula (pouch-like sacs) in the bronchial tree,
and bacterial lung infection, a common cause of COPD exacerbation.

Pathophysiology of COPD
COPD is a complex syndrome comprised of airway inflammation, mucociliary dysfunction and
consequent airway structural changes.
1
Airway inflammation

COPD is characterized by chronic inflammation of the airways, lung tissue and pulmonary blood
vessels as a result of exposure to inhaled irritants such as tobacco smoke.

The inhaled irritants cause inflammatory cells such as neutrophils, CD8 T-lymphocytes, B cells and
+

macrophages to accumulate. When activated, these cells initiate an inflammatory cascade that
2

triggers the release of inflammatory mediators such as tumour necrosis factor alpha (TNF-),
interferon gamma (IFN-), matrix-metalloproteinases (MMP-6, MMP-9), C-reactive protein (CRP),
interleukins (IL-1, IL-6, IL-8) and fibrinogen. These inflammatory mediators sustain the inflammatory
process and lead to tissue damage as well as a range of systemic effects. The chronic inflammation is
present from the outset of the disease and leads to various structural changes in the lung which
further perpetuate airflow limitation. The chronic inflammatory cascade for COPD is illustrated in
Figure 1.

Structural changes

Airway remodeling in COPD is a direct result of the inflammatory response associated with COPD and
leads to narrowing of the airways. Three main factors contribute to this: peribronchial fibrosis, build-up
of scar tissue from damage to the airways and over-multiplication of the epithelial cells lining the
airways. 3,4

Parenchymal destruction is associated with loss of lung tissue elasticity, which occurs as a result of
destruction of the structures supporting and feeding the alveoli (emphysema). This means that the
small airways collapse during exhalation, impeding airflow, trapping air in the lungs and reducing lung
capacity (Figure 2).

Figure 2: Airflow limitation in COPD.

Mucociliary dysfunction

Smoking and inflammation enlarge the mucous glands that line airway walls in the lungs, causing
goblet cell metaplasia and leading to healthy cells being replaced by more mucus-secreting
cells. Additionally, inflammation associated with COPD causes damage to the mucociliary transport
5

system which is responsible for clearing mucus from the airways. Both these factors contribute to
excess mucus in the airways which eventually accumulates, blocking them and worsening airflow
(Figure 3).