Biomedical Engineering Reference
In-Depth Information
previously shown that glucocorticoid suppression of inflammatory genes
requires recruitment of HDAC2 to the activation complex by the GR
(38). This implies that reduced HDAC2 activity will not only increase
inflammatory gene expression but will also cause a reduction in the inhibi-
tory effect of a corticosteroid, dexamethasone, on the expression of these
cytokines. Indeed, we have shown that this is the case in bronchoalveolar
lavage (BAL) macrophages from smokers and in A549 and U937 cells fol-
lowing oxidative stress (H
2
O
2
)(Fig. 3) (94). Furthermore, in peripheral lung
tissue and alveolar macrophage, there is a reduction in HDAC activity and
the expression of HDAC2 in normal smokers and a striking reduction in
patients with COPD (95). We propose that this reduction in HDAC2 pre-
vents corticosteroids from exerting their anti-inflammatory effects in COPD
(Fig. 4) (96). Although the mechanism of HDAC reduction is not yet
Figure 4
Reduction of HDAC2 and corticosteroid resistance in COPD. Stimula-
tion of normal alveolar macrophages activates NF-
k
B and other transcription fac-
tors to switch activate histone acetyltransferase (HAT), histone acetylation and
thus to genes encoding inflammatory proteins, such as TNF
a
, IL-8, and MMP-9.
Corticosteroids reverse this by binding to glucocorticoid receptors and recruiting
HDAC2, which reverses histone acetylation and switches off the activated inflamma-
tory genes. In COPD patients, cigarette smoke activates macrophages, as in normal
subjects, but oxidative stress perhaps acting through the formation of peroxynitrite,
impairs the activity of HDAC2. This amplifies the inflammatory response to NF-
k
B
activation, but also reduces the anti-inflammatory effect of corticosteroids as
HDAC2 is now unable to reverse histone acetylation. (From Ref. 96.)
