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Abstract
Introduction and Objectives Acute exacerbations are a major cause of morbidity and mortality in COPD and current treatments are not very effective. Histone deacetylase 2 (HDAC2) is deficient in stable COPD and is likely to be a mechanism of corticosteroid resistance. It is not known whether impaired HDAC2 activity is an important mechanism in COPD exacerbations.
Methods 9 subjects with GOLD stage II COPD, 10 smokers and 11 non-smokers were infected with rhinovirus 16. Macropahges from induced sputum and bronchoalveolar lavage (BAL) were collected before and following rhinovirus infection and HDAC2 activity measured. Virus load and inflammatory markers were measured in sputum supernantants.
Results At baseline there were no differences in HDAC2 activity in sputum or BAL macrophages between the groups. Following infection HDAC2 activity in the smoking controls and non-smoking controls did not change significantly from baseline (Figure 1). In the COPD subjects there was a trend towards reduced HDAC2 activity in both sputum (ANOVA P = 0.064) and BAL macrophages (Paired t test P = 0.098). Sputum HDAC activity was significantly lower in the COPD subjects compared to non-smokers on days 5 and 42 (P < 0.05), and there was a trend towards lower levels of HDAC in BAL macrophages at infection compared to the non-smokers (P = 0.095) and smokers (P = 0.059) (Figure 1).
Lower sputum macrophage HDAC2 activity at baseline was associated with greater sputum virus load (r = -0.82, P = 0.022) and higher sputum levels of neutrophil elastase (r = -0.81, P = 0.022) and TNF-α (r = -0.79, P = 0.028).HDAC2 activity in BAL macrophages at infection correlated inversely with peak NL virus load (r = -0.8, P = 0.0096), peak sputum GM-CSF (r = -0.67, P = 0.0499), TNF-α (r = -0.72, P = 0.03), neutrophil elastase (r = -0.67, P = 0.0499) and sputum nitrite levels (r = -0.78, P = 0.0125).
Conclusions Following rhinovirus infection HDAC2 activity in airway macrophages is reduced and relates to airway inflammatory markers. Restoring HDAC activity is a potential therapeutic option for COPD exacerbations.