Biomedical Engineering Reference
In-Depth Information
Figure 4
Amplification of lung inflammation in COPD. Normal smokers have an
inflammatory response, which represents the normal response of the respiratory tract
to inhaled irritants. In COPD, this same inflammatory response is markedly ampli-
fied. The molecular mechanisms of this amplification are currently unknown, but
may be determined by genetic factors or latent viral infection. Oxidative stress is
an important amplifying mechanism and may increase the expression of inflamma-
tory genes through impairing the activity of histone deacetylase 2 (HDAC2) which
is needed to switch off inflammatory genes.
(52). Adenovirus infection amplifies the inflammatory response to cigarette
smoke in the airways of guinea pigs (66). Transfection of ElA into a human
epithelial cell line results in increased activation of the transcription factor
NF-
k
B with consequent increased release of IL-8 in response to cell activa-
tion and increased production of TGF-
b
1, providing a molecular mechan-
ism for the amplification in inflammatory response (67,68).
Another molecular mechanism that may underlie the amplification of
inflammation in COPD may involve impaired activity of histone deacety-
lases (HDAC) in alveolar macrophages (69). In macrophages from cigarette
smokers, there is impaired activity of HDAC, which is involved in switching
off the transcription of inflammatory genes by reversing the acetylation of
core histones that is associated with their activation (70,71). In COPD, there
is even more marked reduction in HDAC activity in peripheral lung of
COPD patients than smokers without airway obstruction (72). This may
lead to amplification of the expression of inflammatory genes, as is seen
in alveolar macrophages from patients with COPD (62,73). There is also
increased activation of NF-
k
B in these cells from patients with COPD
(74,75). This reduction in HDAC2 expression and activity also appears to
account for the resistance to corticosteroid seen in COPD patients, thus
linking the two fundamental cellular abnormalities in this disease, namely
amplification of inflammation and corticosteroid resistance.
