Global Initiative for Chronic Obstructive Lung Disease - GOLD

GOLD_WR_05 8/18/05 12:56 PM Page 31
Figure 4-4. Interaction Between
Macrophages, Neutrophils, and Epithelial Cells
• Transforming growth factor-ß (TGF-ß) and epidermal
growth factor (EGF) show increased expression in
epithelial cells and submucosal cells (eosinophils and
fibroblasts) in COPD patients 33 . These mediators
may play a role in airway remodeling (fibrosis and
narrowing) in COPD 34 .
• Endothelin-1 (ET-1), a potent endothelium-derived
vasoconstrictor peptide, is found at increased
concentrations in induced sputum of patients with
COPD 35 . Patients with severe COPD also have
elevated plasma levels of ET-1, which is probably
related to their chronic hypoxemia 36 .
Cigarette smoke activates macrophages and epithelial
cells to produce tumor necrosis factor- (TNF-),
switching on the gene for interleukin-8 (IL-8), which
recruits and activates neutrophils. This process occurs
via the activation of the transcription factor nuclear factor-B
(NF-B).
Printed with permission of Dr. Peter J. Barnes.
Others. Other inflammatory mediators that may be
involved in COPD include the following:
• Macrophage chemotactic protein-1 (MCP-1), a
potent chemoattractant of monocytes, is increased
in the BAL fluid of patients with COPD and smokers
without COPD, but not in ex-smokers or nonsmokers 31 .
Thus, MCP-1 may be involved in macrophage
recruitment into the lungs in smokers.
• Macrophage inflammatory protein-1ß (MIP-1ß) is
increased in the BAL fluid of patients with COPD
compared to smokers, ex-smokers, and nonsmokers 31 .
Macrophage inflammatory protein-1 (MIP-1)
shows increased expression in airway epithelial cells
from COPD patients 3 compared to control smokers.
• Granulocyte-macrophage colony stimulating factor
(GM-CSF) is found at increased concentrations in
the BAL fluid of patients with stable COPD and at
markedly elevated levels during exacerbations 13 . The
number of GM-CSF-immunoreactive macrophages is
also increased in sputum of patients with COPD 32 .
GM-CSF is important for neutrophil survival and may
play a role in enhancing neutrophilic inflammation.
• Neuropeptides, such as substance P, calcitonin
gene-related peptide, and vasoactive intestinal
peptide (VIP), have potent effects on vascular function
and mucus secretion. An increased concentration
of substance P is found in sputum of patients with
chronic bronchitis 37 . One bronchial biopsy study
showed an increase in VIP-immunoreactive nerves
in the vicinity of submucosal glands in patients with
chronic bronchitis, suggesting that this substance
may play a role in mucus hypersecretion 38 . However,
another study showed no significant differences in
the number of nerves immunoreactive for substance
P, calcitonin gene-related peptide, or VIP between
COPD patients and healthy subjects 39 .
• Complement. Activation of the complement pathway
via generation of the potent chemotaxin C5a may
play a significant role in the neutrophil accumulation
seen in the lungs of patients with COPD 40 .
Differences Between Inflammation
in COPD and Asthma
Although inflammation is important in both diseases,
the inflammatory response in COPD is markedly different
from that in asthma, as summarized in Figure 4-5.
However, some patients with COPD also have asthma,
and the inflammation in their lungs may show characteristics
of both diseases.
Since inflammation is a feature of COPD, it follows that
anti-inflammatory therapies may have clinical benefit in
controlling symptoms, preventing exacerbations, and
slowing the progression of the disease. However, the
inflammatory response in COPD appears to be poorly
responsive to the glucocorticosteroids that are effective
anti-inflammatory medications in asthma.
PATHOGENESIS, PATHOLOGY, AND PATHOPHYSIOLOGY 31