Biomedical Engineering Reference
In-Depth Information
soluble TNF receptors in sputum (115). Polymorphisms of the promoter of
the TNF-
a
gene have been associated with increased susceptibility of COPD
in some studies (116-118), but not in others (119-121). This may be related
to the type of COPD studied and has been associated with more severe
disease (122).
The TNF-
a
activates NF-
k
B, which switches on the transcription of
inflammatory genes, including chemokines and proteases, in epithelial cells
and macrophages. In experimental models of emphysema, TNF-
a
appears
to mediate cigarette-induced connective tissue breakdown in the lungs (a
precursor of emphysema) through the release of matrix metalloproteinase-
12 (MMP-12) from macrophages, which then release TNF-
a
from these
cells (123).
Serum concentrations of TNF-
a
and stimulated TNF-
a
production
from peripheral blood monocytes are increased in weight-loosing COPD
patients, suggesting that it may play a role in the cachexia of severe COPD
(124-126). The TNF-
a
inhibits the expression of skeletal muscle proteins via
activation of NF-
k
B (127). This suggests that inhibitors of TNF-
a
might be
useful in reversing the skeletal wasting seen in COPD as well as reducing the
airway inflammatory response (128). Plasma concentrations of TNF-
a
are
increased slightly in COPD patients compared to normal controls during
exercise but this is not associated with any increase in TNF-
a
expression
in skeletal muscle (129).
B. Interleukin-1
b
The IL-1
b
has similar actions to TNF-
a
and is a potent activator of alveolar
macrophages from COPD patients (130). Bronchial epithelial cells in culture
release more IL-1
b
than cells form normal subjects after stimulation with
cigarette smoke (131). However, elevated levels of IL-1 in COPD have not
yet been reported. The IL-1 receptor antagonist (IL-1RA) is an endogenous
inhibitor of IL-1 effects and has been reported to be reduced in asthma. In
COPD macrophages, a reduced secretion of IL-1RA compared to normal
macrophages in response to Chlamydia infection has been described (132).
C.
Interleukin-6
The IL-6 concentrations are increased in induced sputum, bronchoalveolar
lavage, and exhaled breath condensate of COPD patients, particularly dur-
ing exacerbations (133-135). The IL-6 is also increased in the plasma of
COPD patients, especially during exacerbations (136,137). The IL-6 is a
marker of inflammation, as it is activated by NF-
k
B, but its role in inflam-
mation is uncertain as it has both anti-inflammatory and proinflammatory
actions and its effects may be determined by the presence of other cytokines.
