Biomedical Engineering Reference
In-Depth Information
Figure 2
Pivotal role of nuclear factor-
k
B (NF-
k
B) in COPD macrophages. Var-
ious stimuli activate inhibitor of NF-
k
B kinase-2 (IKK-2) which causes translocation
of NF-
k
B to the nucleus where it binds to the promoter region of various inflamma-
tory genes, leading the increased transcription and release of cytokines, chemokines
and proteases, and expression of adhesion molecules.
(61). More studies in human alveolar macrophages are required as there
appear to be important differences in signal transduction pathways between
species. There are also important differences in signalling, depending on the
activating stimulus and the inflammatory gene that is regulated.
C. Histone Acetylation
Inflammatory genes are regulated by acetylation of core histones around
which DNA is wound. Activation of proinflammatory transcription factors,
such as NF-
k
B and AP-1, results in interaction with coactivator molecules
that have intrinsic histone acetyltransferase activity (63). The acetylation
of histone H4 is involved in the activation of inflammatory genes (64) and
this mechanism has been demonstrated in human alveolar macrophages
(65). Histone acetylation is reversed by histone deacetylases (HDAC) which
show reduced activation in alveolar macrophages from COPD patients (65)
and this may account for the increased activation of inflammatory genes and
increased release of inflammatory mediators seen in macrophages from
COPD patients.
