Biomedical Engineering Reference
In-Depth Information
which is chemotactic for neutrophils, is increased in the sputum of patients
with COPD (62).
The elastase, poorly inhibited because of the reduced
a
1
-AT in the defi-
cient subjects, could stimulate the macrophages to release more LTB
4
,
resulting in further neutrophil recruitment, and thereby perpetuating and
amplifying the neutrophil-associated lung damage (63). The concentration
of LTB
4
, which is chemotactic for neutrophils, is increased in the sputum
of patients with COPD (62).
Tumor necrosis factor-
a
(TNF-
a
) is also present in high concentrations
in the sputum of COPD patients and is detectable in bronchial biopsies
specimens, and can induce IL-8 expression in airway cells by activation of
the transcription factor, nuclear factor-
k
B (NF-
k
B) (31). TNF-
a
increases
the expression of ICAM-1, which is increased in COPD and which may
activate macrophages to produce MMP (64).
In COPD, alveolar macrophages and neutrophils play a central role in
destruction of lung parenchyma (65,66). Various proteases break down con-
nective-tissue components, particularly elastin, in lung parenchyma to pro-
duce emphysema. Most attention has focused on neutrophil elastase and
proteinase 3, which are neutrophil-derived serine proteases, and on cathe-
psins, all of which can produce emphysema in laboratory animals (31).
However, there is now increasing evidence that MMPs derived from macro-
phages and neutrophils have a role in patients with emphysema. Studies of
human samples show increases in many proteases, including MMP-1, -2, -8,
-9, and -14 in smoking-related emphysema (67). As discussed above, CD8
รพ
cells are potent producers of IFN-
g
in COPD. IFN-
g
causes emphysema and
alterations in pulmonary protease
=
antiprotease balance when expressed in
pulmonary tissues (54). Three MMPs degrade elastin: MMP-2, -9, and
-12. Particularly, MMP-9 has been found elevated in homogenates of lung
removed from patients underwent to lung volume reduction surgery, which
represents samples obtained by advance stage of emphysema (67). Homoge-
nates of lung removed in volume reduction reveal MMP-9-related elastolytic
and gelatinolytic activity and significant elevations in MMP-9, with no sig-
nificant increase in neutrophil elastase by ELISA (68). There is an increase
in the activity of MMP-9 and MMP-2 in the lung parenchyma of patients
with emphysema. The role of MMP-9 in the pathogenesis of emphysema
is likely to be complex;
a
-antitrypsin can be cleaved by MMP-9. Increased
chemotactic activity of BALF is associated with the development of smok-
ing-related emphysema (69), and potentiation of IL-8 by MMP-9 could
amplify the alveolar inflammation and destruction in smokers who develop
emphysema (70).
Also, oxidative stress may have an important role in COPD. In smo-
kers and in COPD patients, there is an oxidant
=
antioxidant imbalance in
favour of oxidants (71). The presence of oxidative stress has been assessed
by measuring markers of the effects of radicals on lung biomolecules such
