Biomedical Engineering Reference
In-Depth Information
certain, we propose that it may be mediated via oxidative stress. Exhaled
markers of oxidative stress, such as 8-isoprostane and ethane, are increased
in normal smokers with a much greater increase in patients with COPD,
even when they have stopped smoking (97,98). Oxidative stress and cigarette
smoking increase histone acetylation and switch on inflammatory gene tran-
scription (15,99). We propose that oxidative stress impairs the function of
HDAC2, resulting in resistance to corticosteroids and this has been demon-
strated in an epithelial cell line, monocytic cell line, and primary epithelial
cells from healthy volunteer in vitro (94). Furthermore, oxidative stress also
reduces the inhibitory effect of corticosteroids on cytokine release in vitro,
an effect that is mimicked by a nonspecific HDAC inhibitor trichostatin
A (94). Thus, by impairing the function of HDAC2, oxidative stress may
both amplify inflammation and impair the anti-inflammatory action of
corticosteroids (Figs. 3 and 4) (96).
However, the mechanisms whereby oxidative stress leads to this
impairment in activity of HDAC remain to be determined by future studies.
One possibility is that oxidative stress in the presence of increased nitric
oxide (NO) formation may generate peroxynitrite, which then nitrates tyro-
sine residues on HDAC or associated proteins. In COPD, there is certainly
evidence for nitrotyrosine formation in alveolar macrophages (100). This
could be directly investigated by measuring nitration of tyrosine residues
on HDAC in vitro and in COPD cells and tissues. Another possibility is
phosphorylation of specific HDAC, thus changing their function by some
kinases, which are activated by oxidative stress, such as Akt
=
PKB,
phosphoinositol 3 kinase, and p38 MAPK (101-103).
VI. THERAPEUTIC IMPLICATIONS
The proposed mechanism of steroid resistance in COPD involving a
reduction in HDAC2 activity and expression as a consequence of oxidative
stress has important therapeutic implications. We predict that there are
several strategies that might overcome steroid resistance in COPD so that
corticosteroids become able to switch off the multiple inflammatory cyto-
kines, chemokines, and proteases that mediate the disease. We predict that
effective antioxidants that are able to neutralize oxidative stress would
increase the response to corticosteroids. However, currently available anti-
oxidants are unlikely to reduce the high level of oxidative stress in severe
COPD and more potent drugs, or perhaps an inhaled delivery, are needed
in the future. If peroxynitrite formation mediates the effects of oxidative
stress, then inhibiting inducible NO synthase, which is upregulated in COPD
macrophages (100) or peroxynitrite scavenger (104,105) might be a more
efficient approach. Potent, selective, and long-lasting inducible NO synthase
inhibitors are now in clinical development (106).
