CD8-driven [29–31]. This is an important distinction, since it affects drug efficacy.
There is now plenty of evidence that inhaled corticosteroids are effective against the
eosinophilic inflammation observed in asthma but largely ineffective against the
primarily neutrophilic inflammation encountered in COPD [32, 33]. Even more so,
currently no pharmaceutical agent effectively stops the progression of COPD,
leading to approximately three million deaths per year [30].
2.2 Deacetylase and Acetyltransferase Expression in COPD
In peripheral lung tissue, alveolar macrophages, and bronchial-biopsy specimens
from COPD patients, HDAC activity is decreased compared to healthy non-smokers
[34]. Notably, there is a marked and selective reduction in the expression of HDAC2
in patients with very severe COPD. They express less than 5% of HDAC2 of
non-smokers, whereas smaller reductions were observed for the expression of
HDAC5 and HDAC8. Reduced HDAC2 activity is correlated with disease severity
and increased expression of inflammatory genes such as IL-8, which is most likely
caused by increased histone H4 acetylation at the IL-8 promoter [34]. Reduced
HDAC activity is also related to corticosteroid resistance, a characteristic feature of
COPD. The expression of HDAC1, HDAC3, HDAC4, HDAC6, and HDAC7 was
found unaltered. The expression and activity of HDAC9, HDAC10, and HDAC11
and most of the sirtuins in COPD are unknown, although sirtuin 1 activity is
decreased [35]. The expression of acetyltransferases is largely unaffected.
2.3 Causes and Consequences of a Decrease in HDAC2
Expression in COPD
The decrease in HDAC2 activity is believed to be partly caused by nitration of one or
two tyrosine residues of HDAC2 through the formation of peroxynitrite, which is
generated by a reaction between superoxide anions and nitric oxide upon inhalation
of noxious particles [36]. Nitration in turn triggers ubiquitination and subsequent
proteosomal degradation [37]. While both HDAC1 and HDAC2 are modified by
such reactive nitrogen species, only the level of HDAC2 is decreased, possibly by
selective ubiquitin tagging of nitrated HDAC2 [37]. The enzymes responsible for
ubiquitination of HDAC1 are unknown but differ from those of HDAC2. Additionally, reactive oxygen species in inflamed lung tissue activate the phosphoinositide-3kinase (PI3K) pathway, causing phosphorylation of HDAC2’s serine residues by
either PI3K itself or other downstream kinases, which similarly leads to its ubiquitinproteosomal breakdown (Fig. 1b) [38].
434
M. R. H. Zwinderman et al.
There is now plenty of evidence that inhaled corticosteroids are effective against the
eosinophilic inflammation observed in asthma but largely ineffective against the
primarily neutrophilic inflammation encountered in COPD [32, 33]. Even more so,
currently no pharmaceutical agent effectively stops the progression of COPD,
leading to approximately three million deaths per year [30].
2.2 Deacetylase and Acetyltransferase Expression in COPD
In peripheral lung tissue, alveolar macrophages, and bronchial-biopsy specimens
from COPD patients, HDAC activity is decreased compared to healthy non-smokers
[34]. Notably, there is a marked and selective reduction in the expression of HDAC2
in patients with very severe COPD. They express less than 5% of HDAC2 of
non-smokers, whereas smaller reductions were observed for the expression of
HDAC5 and HDAC8. Reduced HDAC2 activity is correlated with disease severity
and increased expression of inflammatory genes such as IL-8, which is most likely
caused by increased histone H4 acetylation at the IL-8 promoter [34]. Reduced
HDAC activity is also related to corticosteroid resistance, a characteristic feature of
COPD. The expression of HDAC1, HDAC3, HDAC4, HDAC6, and HDAC7 was
found unaltered. The expression and activity of HDAC9, HDAC10, and HDAC11
and most of the sirtuins in COPD are unknown, although sirtuin 1 activity is
decreased [35]. The expression of acetyltransferases is largely unaffected.
2.3 Causes and Consequences of a Decrease in HDAC2
Expression in COPD
The decrease in HDAC2 activity is believed to be partly caused by nitration of one or
two tyrosine residues of HDAC2 through the formation of peroxynitrite, which is
generated by a reaction between superoxide anions and nitric oxide upon inhalation
of noxious particles [36]. Nitration in turn triggers ubiquitination and subsequent
proteosomal degradation [37]. While both HDAC1 and HDAC2 are modified by
such reactive nitrogen species, only the level of HDAC2 is decreased, possibly by
selective ubiquitin tagging of nitrated HDAC2 [37]. The enzymes responsible for
ubiquitination of HDAC1 are unknown but differ from those of HDAC2. Additionally, reactive oxygen species in inflamed lung tissue activate the phosphoinositide-3kinase (PI3K) pathway, causing phosphorylation of HDAC2’s serine residues by
either PI3K itself or other downstream kinases, which similarly leads to its ubiquitinproteosomal breakdown (Fig. 1b) [38].
434
M. R. H. Zwinderman et al.