Biomedical Engineering Reference
In-Depth Information
cascade including cytokines, chemokines, growth factors, enzymes, recep-
tors, and adhesion molecules (7-9). Especially, increased production of
tumor necrosis factor-
a
(TNF
a
), interferon-
g
(IFN
g
), interleukin-8 (IL-8),
macrophage inflammatory protein l
a
(MlP-l
a
), monocyte chemoattractant
protein I (MCP-1), GRO
a
, matrix metalloproteinase (MMP)-9 are found
in COPD (7-9).
A. Transcription Factors
Increased inflammatory gene transcription is regulated by pro-inflammatory
transcription factors, such as nuclear factor-
k
B (NF-
k
B) and activator
protein-1 (AP-1). There is evidence that these transcriptional factors are
activated in COPD and also in cells exposed to oxidative stress (10-13).
For example, NF-
k
B appears to be activated in sputum macrophages during
exacerbations of COPD (11). Bronchial biopsies in smokers with normal
lung function and COPD patients show increased expression of NF-
k
B,
p65 protein, predominantly in the bronchial epithelium. Cigarette smoke
and hydrogen peroxide (H
2
O
2
) induce marked NF-
k
B and AP-1 activation
in epithelial cells (13-15) and these transcription factors regulate many of
the inflammatory genes that are abnormally expressed in corticosteroid-
resistant (CR) asthma and steroid-insensitive Crohn's disease (1,2). NF-
k
B
is ubiquitously expressed and is able to not only control induction of inflam-
matory genes in its own right but also can enhance the activity of other cell
and signal-specific transcription factors (16). In addition, it is a major target
for corticosteroids (16). NF-
k
B is activated by all the stimuli relevant to
chronic respiratory diseases including cytokines, such as TNF
a
and inter-
leukin-l
b
(IL-l
b
), viruses, and oxidative stress including cigarette smoke
(14,16,17). Activation of cell surface receptors leads to phosphorylation of
receptor-associated kinases. These kinases in turn phosphorylate specific
intracellular kinases (inhibitor of NF-
k
B kinase; IKK). Phosphorylation
of IKKs results in phosphorylation of the NF-
k
B cytoplasmic inhibitor
(I-
k
B
a
), which targets I-
k
B
a
for proteosomal degradation. This releases
NF-
k
B from its inactive state enabling nuclear translocation and binding
to specific DNA response elements within the regulatory regions of respon-
sive genes (18).
AP-1 is a transcription factor complex that is formed by dimerization
of members of the Fos (c-Fos, Fral, and Fra2) and Jun (c-Jun, Jun B, and
Jun D) protooncogene families and is defined by binding to the phorbol
ester 12-O-tetradecanoylphorbol-13-acetate (TPA)-response element
(TRE) (19,20). In the resting cells, AP-1 is composed of dimers of the Jun
family and has weak DNA binding and gene transactivating activities.
When the cell is activated, the components of AP-1 change rapidly to Fos:-
Jun heterodimers of which c-Fos:c-Jun is the most abundant and is much
more active than the resting homodimer. Inducible AP-1 is formed after
