2.4 Restoring HDAC2 Activity in COPD as a Therapeutic
Strategy
Given the observed decrease in HDAC2 expression, and the resulting increase in
IL-8 and steroid resistance, restoring its activity is the first and most logical therapeutic aim. To this end, a low concentration of theophylline (10 μM) has been shown
to increase HDAC activity both in vitro and ex vivo [41, 42]. It is unclear how
exactly theophylline increases HDAC activity, but it is thought to occur through the
inhibition of PI3K [43]. At higher concentrations (>10 μM), theophylline inhibits
phosphodiesterases and antagonizes adenosine receptors, for which it has been used
to treat airway diseases for decades, with the main result being airway smooth
muscle relaxation [44]. Interestingly, theophylline’s ability to restore HDAC activity
is lost at such higher concentrations [42]. It should be noted that administration of a
low dose of theophylline alone did not significantly reduce steroid-resistant inflammation in vivo [43]. Only combined with corticosteroids, a positive effect was
observed, effectively alleviating steroid resistance.
A hypothetical novel way of restoring HDAC2 activity would be to inhibit a
functionally opposing acetyltransferase. This is based on the presumption that an
acetyltransferase may have the same substrates as HDAC2, but so far this has not
been confirmed. Even more so, the development of clinically useful acetyltransferase
inhibitors has fallen behind that of HDACi partly due to the low druggability of the
catalytic domain of acetyltransferases. Consequently, only a few acetyltransferase
inhibitors exist, and none have been tested in COPD. Other ways to restore HDAC
activity are focused on inhibition of PI3K similar to theophylline or on the reduction
of oxidative stress and thus peroxynitrite, potentially by the administration of
antioxidants [45]. In the latter case, reducing the exposure to harmful particles
works in a similar way. The success of such a strategy is exemplified by the fact
that in COPD patients who smoke, smoking cessation has been shown to be the
single most effective approach for slowing or halting disease progression [46, 47].
2.5 Targeting HDAC Isoenzymes in COPD
Given the decreased activity of HDAC2 in COPD and an observed add-on effect of
theophylline as a HDAC activator in corticosteroid therapy, attempts to decrease
HDAC activity with HDACi in COPD seem counterintuitive. On the other hand,
diverse chemical classes of HDACi demonstrated therapeutic potential in several
animal models of inflammation, such as colitis [48], multiple sclerosis [49], and
arthritis [50]. The mentioned models are not necessarily predictive of an antiinflammatory effect in COPD, as the underlying inflammatory dynamics are often
very different. However, entinostat, a HDAC1-, HDAC2-, and HDAC3-selective
inhibitor (Fig. 2), was recently found to attenuate inflammation in a mouse model of
COPD [51]. The observed positive effect was connected to a decrease in neutrophil
436
M. R. H. Zwinderman et al.
Strategy
Given the observed decrease in HDAC2 expression, and the resulting increase in
IL-8 and steroid resistance, restoring its activity is the first and most logical therapeutic aim. To this end, a low concentration of theophylline (10 μM) has been shown
to increase HDAC activity both in vitro and ex vivo [41, 42]. It is unclear how
exactly theophylline increases HDAC activity, but it is thought to occur through the
inhibition of PI3K [43]. At higher concentrations (>10 μM), theophylline inhibits
phosphodiesterases and antagonizes adenosine receptors, for which it has been used
to treat airway diseases for decades, with the main result being airway smooth
muscle relaxation [44]. Interestingly, theophylline’s ability to restore HDAC activity
is lost at such higher concentrations [42]. It should be noted that administration of a
low dose of theophylline alone did not significantly reduce steroid-resistant inflammation in vivo [43]. Only combined with corticosteroids, a positive effect was
observed, effectively alleviating steroid resistance.
A hypothetical novel way of restoring HDAC2 activity would be to inhibit a
functionally opposing acetyltransferase. This is based on the presumption that an
acetyltransferase may have the same substrates as HDAC2, but so far this has not
been confirmed. Even more so, the development of clinically useful acetyltransferase
inhibitors has fallen behind that of HDACi partly due to the low druggability of the
catalytic domain of acetyltransferases. Consequently, only a few acetyltransferase
inhibitors exist, and none have been tested in COPD. Other ways to restore HDAC
activity are focused on inhibition of PI3K similar to theophylline or on the reduction
of oxidative stress and thus peroxynitrite, potentially by the administration of
antioxidants [45]. In the latter case, reducing the exposure to harmful particles
works in a similar way. The success of such a strategy is exemplified by the fact
that in COPD patients who smoke, smoking cessation has been shown to be the
single most effective approach for slowing or halting disease progression [46, 47].
2.5 Targeting HDAC Isoenzymes in COPD
Given the decreased activity of HDAC2 in COPD and an observed add-on effect of
theophylline as a HDAC activator in corticosteroid therapy, attempts to decrease
HDAC activity with HDACi in COPD seem counterintuitive. On the other hand,
diverse chemical classes of HDACi demonstrated therapeutic potential in several
animal models of inflammation, such as colitis [48], multiple sclerosis [49], and
arthritis [50]. The mentioned models are not necessarily predictive of an antiinflammatory effect in COPD, as the underlying inflammatory dynamics are often
very different. However, entinostat, a HDAC1-, HDAC2-, and HDAC3-selective
inhibitor (Fig. 2), was recently found to attenuate inflammation in a mouse model of
COPD [51]. The observed positive effect was connected to a decrease in neutrophil
436
M. R. H. Zwinderman et al.