Biomedical Engineering Reference
In-Depth Information
inflammation, the balance between genes for inflammatory mediators and
antioxidant
=
phase II enzymes may be tipped in favor of pro-inflammatory
mediators (Fig. 13).
XVII. CHROMATIN REMODELING (HISTONE ACETYLATION
AND DEACETYLATION) AND GLUCOCORTICOID
INEFFICACY IN RESPONSE TO SMOKING
Tightly bound DNA around a nucleosome core (histone proteins) sup-
presses gene transcription by decreasing the accessibility of transcription
factors, such as NF-
k
B and AP-1 to the transcriptional complex. Acetyla-
tion of lysine residues in the N-terminal tails of the core histone proteins
results in uncoiling of the DNA, allowing increased accessibility for tran-
scription factor binding. Histone acetylation is reversible and is regulated
by a group of acetyltransferases (HATs) which promote acetylation, and
deacetylases (HDACs) which promote deacetylation.
Recently, Ito et al. (100) have shown a role for histone acetylation and
deacetylation in IL-l
b
-induced TNF-
a
release in alveolar macrophages
derived from cigarette smokers. They have also suggested that oxidants
may play an important role in the modulation of HDAC and inflammatory
cytokine gene transcription. Furthermore, we have shown that both cigar-
ette smoke
=
H
2
O
2
and TNF-
a
caused an increase in histone acetylation
(HAT activity) leading to IL-8 expression in monocytes and alveolar
epithelial cells in vitro and in vivo in rat lungs (101-103).
It has been suggested that oxidative stress may have a role in the poor
efficacy of corticosteroids in COPD. It has been shown that glucocorticoid
suppression of inflammatory genes requires recruitment of HDAC-2 to the
transcription activation complex by the glucocorticoid receptor (100,103).
This results in deacetylation of histones and a decrease in inflammatory gene
transcription. A reduced level of HDAC-2 was associated with increased pro-
inflammatory response and reduced responsiveness to glucocorticoids in
alveolar macrophages obtained from smokers and in vivo in rat lungs
exposed to cigarette smoke (101-103). Culpitt et al. (104) have shown that
cigarette smoke solution stimulated release of IL-8 and GM-CSF, which
was not inhibited by dexamethasone, in alveolar macrophages obtained from
patients with COPD compared to that of smokers. They suggested that the
lack of efficacy of corticosteroids in COPD might be due to steroid insensi-
tivity of macrophages in the respiratory tract. Thus, the cigarette smo-
ke
=
oxidant-mediated reduction in HDAC-2 levels in alveolar epithelial cells
and macrophages will not only increase inflammatory gene expression but
will also cause a decrease in glucocorticoid function in patients with COPD
(105). This may be one of the potential reasons for the failure of glucocorti-
coids to function effectively in reducing inflammation in COPD (Fig. 14).
