The reasons for the reduction in HDAC, particularly HDAC-2, in COPD are not yet completely understood. However, there is increasing evidence that this may be due to inactivation of the enzyme of oxidative and nitrative stress13–14 (Fig 3
). Oxidative stress is increased in COPD and increases with disease severity.16 Nitrative stress is also increased in peripheral lung of COPD patients.17 Oxidative and nitrative stress lead to the rapid formation of peroxynitrite, which nitrates selected tyrosine residues on certain proteins. HDAC-2, but not other isoforms of HDAC, shows increased tyrosine nitration in macrophages and peripheral lung of COPD patients, and this is correlated with increased expression of IL-8. Nitration of proteins such as HDAC-2 leads to their ubiquitination, which marks them for degradation by the proteasome, resulting in the very low levels of HDAC-2 protein in the lungs of patients with severe COPD. The high level of oxidative/nitrative stress in COPD lungs, particularly as the disease progresses, may therefore result in increased tyrosine nitration and impaired HDAC-2 function and reduction in expression, which thereby leads to increased expression of inflammatory genes and impaired responses to corticosteroids.