Biomedical Engineering Reference
In-Depth Information
Figure 14
Model showing the possible mechanism of histone acetylation by oxida-
tive stress and its repression by cortico steroids (GCs), leading to inhibition of gene
transcription. MAP kinase signaling pathways may be activated by oxidative stress
leading to histone acetylation. Direct interaction between co-activators (HAT),
histone deacetylase, and the glucocorticoid receptor (GR) may result in repression
of the expression of pro-inflammatory genes. HDAC forms a bridge with HAT to
inhibit gene transcription. However, when the HDAC is inhibited by oxidants or
the NF-kB subunit p65 is acetylated, steroids may not be able to recruit HDACs into
the transcriptional complex to inhibit pro-inflammatory gene expression.
XVIII. ANTIOXIDANT THERAPEUTIC INTERVENTIONS
It is now evident that oxidant
=
antioxidant balance is altered in favor of oxi-
dants in smokers, which plays an important role in the pathogenesis of
COPD. Therefore, it would be logical to propose the rationale of antioxi-
dant therapy in ameliorating the increased oxidative stress and consequently
the inflammatory response in COPD. There are various options to enhance
the lung antioxidant screen (Table 4).
A. Phosphodiesterase 4 Inhibitor
One approach is to target the inflammatory response by reducing the seques-
tration or migration of leukocytes from the pulmonary circulation into the
airspaces. Possible therapeutic options for this are drugs that alter cell
