Biomedical Engineering Reference
In-Depth Information
polymerase and the suppression of inflammatory gene transcription. This
mechanism can account for the anti-inflammatory effect of corticosteroids
in asthma and other inflammatory diseases. Thus, in bronchial biopsies of
untreated asthmatic and COPD patients, there is an increase in HAT activ-
ity, which is reversed in patients controlled on inhaled corticosteroids (39).
This new understanding of the anti-inflammatory mechanisms of corticos-
teroids may now help us to understand how these become impaired in
COPD (Fig. 1).
IV. CORTICOSTEROID INSENSITIVITY IN COPD
Although inhaled corticosteroids (ICS) are highly effective in asthma, they
provide much less clinical benefit in COPD, despite the fact that airway
and lung inflammation is present (4,40). Recently, four large 3-year studies
of ICS in COPD have been published (41-44). The results showed that ICS
do not affect the rate of decline in FEV
1
, which was the primary endpoint in
all of the studies. This means that long-term treatment with high doses of
ICS fails to reduce the accelerated progression of airway obstruction in
COPD, which is thought to be a consequence of a chronic inflammatory
process (45). Analysis of the secondary endpoints (such as reducing in symp-
toms and in exacerbations) in some of the studies suggests ICS at high dose
may benefit for some patients with COPD. Thus, in airway inflammation in
COPD, high doses of inhaled or even oral corticosteroids fail to reduce
inflammatory cells, cytokines, or proteases (46-48) though in asthma these
are suppressed by low doses of inhaled corticosteroids in most patients.
Alveolar macrophages play a critical role in orchestrating the chronic
inflammation in COPD through the release of proteases such as MMP-9,
inflammatory cytokines such as TNF
a
, and chemokines such as IL-8 that
attract neutrophils into the airways. Corticosteroids effectively suppress
the release of these inflammatory mediators in alveolar macrophages from
normal nonsmokers, but are less effective in cells from smokers with normal
lung function and virtually ineffective in macrophages from patients with
COPD (Fig. 2) (49,50). We also found that H
2
O
2
, an oxidative stress,
mimicked this in U937 monocytic cell line, and enhanced lipopolysaccharide
(LPS)-induced IL-8 production and decreased the inhibitory effect of
steroids (Fig. 2). This suggests that alveolar macrophages have developed
resistance to corticosteroids in patients with COPD.
V. MOLECULAR MECHANISMS UNDERLYING
CORTICOSTEROID INSENSITIVITY
At a molecular level, resistance to the anti-inflammatory effects of corticos-
teroids is reported to be induced by several mechanisms in asthma and other
diseases. The reduction in corticosteroid responsiveness observed in cells
