Biomedical Engineering Reference
In-Depth Information
albeit to a lesser extent than in macrophages from normal smokers. The rea-
sons for resistance to corticosteroids in COPD and to a lesser extent macro-
phages from smokers may be the marked reduction in activity of histone
deacetylase-2 (HDAC2) (65), which is recruited to activated inflammatory
genes by activated glucocorticoid receptors to switch off inflammatory genes
(64) (Fig. 3). The reduction in HDAC2 activity in macrophages is correlated
with increased secretion of cytokines like TNF-
a
and IL-8 and reduced
response to corticosteroids. The reduction of HDAC2 activity in COPD
patients may be mediated through oxidative stress and peroxynitrite
formation (79).
Figure 3
Stimulation of normal alveolar macrophages activates nuclear factor-
k
B
(NF-
k
B) and other transcription factors to switch on histone acetyltransferase lead-
ing to histone acetylation and subsequently to transcription of genes encoding
inflammatory proteins, such as tumour necrosis factor-
a
(TNF-
a
), interleukin-8
(IL-8), and matrix metalloproteinase-9 (MMP-9). Corticosteroids reverse this by
binding to glucocorticoid receptors (GR) and recruiting histone deacetylase-2
(HDAC2). This reverses the histone acetylation induced by NF-
k
B and switches
off the activated inflammatory genes. In COPD patients, cigarette smoke activates
macrophages, as in normal subjects, but oxidative stress (perhaps acting through
the formation of peroxynitrite) impairs the activity of HDAC2. This amplifies the
inflammatory response to NF-
k
B activation, but also reduces the anti-inflammatory
effect of corticosteroids as HDAC2 is now unable to reverse histone acetylation.
