Biomedical Engineering Reference
In-Depth Information
Another approach would be administration of low doses of theophyl-
line, which have recently been shown to increase the activity of HDAC
through a novel mechanism independent of phosphodiesterase inhibition
and adenosine antagonism (107) (Fig. 5). In vitro theophylline at lower than
therapeutic concentrations is able to restore the reduced HDAC activity
induced by oxidative stress and restore steroid responsiveness. Alternatively,
it may be possible to use MAP kinase inhibitors as steroid-sparing agents
reducing the dose of corticosteroid needed to obtain effective therapy.
Recent preliminary data suggest that the combination of long-acting
b
adre-
nergic receptor agonist (LABA) and inhaled steroid may be more effective
than monotherapy of inhaled steroid in COPD (40), although the magnitude
of the improvement in lung function are smaller than those reported in the
earlier asthma studies. Ligand-independent activation of GR by LABAs has
been demonstrated in a human cell line in vitro (108). Long-acting
b
adre-
nergic receptor agonist also may affect some kinases involved in the regula-
tion of GR function (109,110), or even indirectly modify HAT
=
HDAC
activity.
Figure 5
Effect of theophylline on HDAC activity and H
2
O
2
-induced steroid insen-
sitivity in A549 cells. (A) Theophylline and dexamethasone were added to nuclear
extracts containing HDAC proteins from A549 cells. Total HDAC activity was mea-
sured by
3
H-acetic acid release from labelled histones. Theophylline dose-
dependently increased HDAC activity up to 10
5
M, whereas dexamethasone
showed no effect.
:p
<
0.01,
:p
<
0.05. (B) A549 cells were stimulated with IL-l
b
(l ng
=
mL) after 4-hr pretreatment of H
2
O
2
(100
m
M). Theophylline was treated
20 min before and dexamethasone was treated 30 min before IL-1
b
stimulation.
Granulocyte-macrophage colony-stimulating factor production was measured with
ELISA. Dexamethasone (10
10
M) or theophylline (10
5
M) alone was less effective
in IL-1
b
stimulation under H
2
O
2
treatment, but low dose theophylline enhanced the
suppressive effect of dexamethasone. This effect was attenuated by trichostatin
A (TSA), an HDAC inhibitor, indicating that theophylline can attenuate oxidative
stress-induced steroid resistance via an increase in HDAC activity. (From Ref. 107.)
