Biomedical Engineering Reference
In-Depth Information
III. REACTIVE OXYGEN AND NITROGEN SPECIES
Oxidative and nitrative stresses are an important feature of COPD and there
is increasing evidence that they are involved in its pathophysiology.
A. Reactive Oxygen Species
There is compelling evidence for increased oxidative stress in patients with
COPD (28,29) (see Chapter 12). Cigarette smoke contains a high concentra-
tion of reactive oxygen species (ROS) (10
17
moles
=
puff) and inflammatory
cells, such as activated macrophages and neutrophils, also contribute. Evi-
dence for increased oxidative stress in COPD is provided by demonstration
of increased concentrations of hydrogen peroxide (H
2
O
2
) in expired conden-
sates (30), increased 8-isoprostane levels in expired condensate (31) and
ethane, a product of lipid peroxidation, in expired air (32). These markers
of oxidative stress are further increased during exacerbations (18,30).
The increased oxidative stress in COPD may have several deleterious
effects; oxidation of antiproteases, such as
a
1
-antitrypsin (
a
1
-AT) and secre-
tory leukoprotease inhibitor (SLPI), may reduce the antiprotease shield, and
may directly activate matrix metalloproteinases (MMP), resulting in
increased proteolysis. H
2
O
2
directly constricts airway smooth muscle
in vitro (33) and hydroxyl radicals (OH
) potently induce plasma exudation
in airways (34). Oxidants also activate NF-
k
B, which orchestrates the
expression of multiple inflammatory genes, including IL-8, TNF-
a
,and
MMP-9. The ROS are normally counteracted by endogenous (glutathione,
uric acid, bilirubin) and exogenous (vitamin C and vitamin E from diet)
antioxidants. There is evidence for a reduction in antioxidant defenses in
patients with COPD which may further enhance oxidative stress (28,29).
B. Nitric Oxide
Nitric oxide (NO) is generated in COPD from the enzyme inducible NO
synthase (iNOS), which is expressed in macrophages and lung parenchyma
of patients with COPD, particularly in patients with severe disease (35,36).
The NO is markedly increased in exhaled breath of patients with mild
asthma reflecting the inflammatory process in the airways, but in patients
with COPD exhaled NO levels are little raised above normal (37-39), but
are more clearly increased during exacerbations (37,40).
C. Peroxynitrite
This may be because exhaled NO levels are depressed by cigarette smoking
and oxidative stress, as NO combines avidly with ROS to form peroxyni-
trite. This is supported by the fact that nitrate concentrations, formed by
metabolism of peroxynitrite, are increased in breath condensate and sputum
of cigarette smokers and patients with COPD (41,42). There is also a
