Abstract
The expression of HDAC2 is reported as reduced in chronic obstructive pulmonary disease (COPD). We assessed HDAC2 expression within the airways of smokers and subjects with COPD and effects of inhaled corticosteroids (ICS), using immuno-histology to contrast with previous molecular methodology.Endobronchial biopsies (ebb) from current smokers with COPD (COPD-CS; n = 15), ex-smokers with COPD (COPD-ES; n = 17), smokers with normal lung function (NS; n = 16) and normal controls (NC; n = 9) were immunostained for HDAC2. A double-blinded, randomized, placebo-controlled 6 months intervention study assessed effects of ICS on HDAC2 in 34 COPD subjects.There was no difference in epithelial HDAC2 staining in all groups. There was a significant reduction in total cell numbers in the lamina propria (LP) in COPD-CS and NS (p<0.05). LP cellularity correlated inversely with smoking history in COPD-CS (R = −0.8, p<0.003). HDAC2 expression increased markedly in NS (p<0.001); in contrast COPD-CS was associated with suppressed signal (p<0.03), while normal in COPD-ES. ICS did not affect HDAC2 cell staining.Our findings suggest that airway HDAC2 expression is increased in the LP by smoking itself, but is reduced in COPD. Ex-smokers have normalised HDAC2 cell expression, but ICS had no effect. The paper emphasise the pit-falls of relying on molecular data alone to define airway changes.Clinical Trial Registration Information:Name of registryThe Australian New Zealand Clinical Trials Registry (ANZCTR)Registry number ACTRN12612001111864
Highlights
chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible, usually progressive and associated with an abnormal inflammatory response of the lung airways in response to noxious particles and gases [1]
HDAC2 expression in the airway epithelium HDAC2 expression in the airway epithelium was not significantly different between the groups (Figure 2 and 3), [median; normal controls (NC) 25.3% (1.1%–29.3%); NS 24.9% (10.2%– 29.6%); COPD-CS 20.8% (8.6%–31.2%); COPD-ex-smokers with COPD (ES) 24.7% (0%– 30.6%) p = 0.7], it was reduced on average in the current smoking COPD but with wide inter-subject scatter
The airway epithelium showed strong HDAC2 expression, but this was not significantly different between the groups, COPD current smokers showed a slight decrease in average HDAC2 staining, which mirrored that found in the lamina propria (LP)
Summary
COPD is a disease state characterized by airflow limitation that is not fully reversible, usually progressive and associated with an abnormal inflammatory response of the lung airways in response to noxious particles and gases [1]. The control of airway inflammation and response to airway oxidative stress is highly complex and many overlapping mechanisms are involved. Airway inflammation in the airways responds [3] to therapeutic corticosteroids but only relatively poorly in COPD even though steroids have been shown to have some important specific beneficial effect clinically both in the short and long term [4,5]. There is evidence that relative corticosteroids anti-inflammatory resistance in COPD may be partly due to decrease in histone deacetylase activity, and especially the type-2 enzyme (HDAC2) [6,7]. Though exact mechanisms are still not clearly understood, it is suggested that this may involve oxidative modulation of HDACs by nitrosylation on distinct tyrosine residues in response to tobacco smoke [2]
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