Biomedical Engineering Reference
In-Depth Information
Polymorphisms of various genes, in particular oxidant and antioxidant
responsive genes, have been shown to be more prevalent in smokers who
develop COPD. Microsomal epoxide hydrolase (an enzyme involved in
the metabolism of highly reactive epoxide intermediates which are present
in cigarette smoke) has been shown to be polymorphic in emphysema
(80). The proportion of individuals with slow microsomal epoxide hydrolase
activity (homozygotes) was significantly higher in patients with COPD and a
subgroup of patients shown pathologically to have emphysema (COPD
22%; emphysema 19%), compared with control subjects (6%) (80,81). Simi-
larly, the polymorphism of another antioxidant gene-glutathione-S-transfer-
ase is associated with decline in lung function in smokers (81). Variations in
the levels of glutathione and the genetic polymorphism of its synthesizing
gene
g
-GCS, and HO-1 represent new oxidative stress susceptibility factor
in the pathogenesis in COPD (44,82). It may be that a panel of ''susceptibil-
ity gene'' polymorphisms, of functional significance in enzymes involved in
xenobiotic metabolism or antioxidant enzyme genes may allow individuals
to be identified as being susceptible to the effects of cigarette smoke.
XVI. OXIDATIVE STRESS, NF-
k
B ACTIVATION, AND GENE
EXPRESSION
A. NF-
k
B Activation
It is well known that various inflammatory genes, such as those for the
cytokines, IL-8, TNF-
a
, and nitric oxide (iNOS), are regulated by NF-
k
B.
NF-
k
B exists as a heterodimeric complex usually of p50 and p65
=
RelA sub-
units. In unstimulated cells, NF-
k
B is found in the cytoplasm as an inactive
non-DNA binding form, associated with an inhibitor protein called inhibi-
tory
k
B(I
k
B) which masks the nuclear translocation signal and so prevents
NF-
k
B from entering the nucleus. Many stimuli, including cytokines and
oxidants, activate NF-
k
B, resulting in ubiquitination, cleaving of I
k
B from
NF-
k
B and the destruction of I
k
B in the proteosome (Fig. 12). The released
NF-
k
B dimer can then be translocated into the nucleus and activate target
genes by binding with high affinity to
k
B elements in their promoters. These
critical events in the inflammatory response are redox sensitive. Recently, Di
Stefano et al. (83) have demonstrated increased expression of p65 protein of
NF-
k
B in bronchial epithelium of smokers and patients with COPD. The
increased expression of p65 in epithelial cells was correlated with the degree
of airflow limitation in patients with COPD. Similarly, Caramori et al. (84)
have shown the p65 subunit of NF-
k
B was increased in sputum macro-
phages but not in sputum neutrophils during exacerbations of COPD
suggesting that inflammatory response can be seen in diverse cell popula-
tion. The activation of NF-
k
B in monocytes
=
macrophages can then trigger
the release of pro-inflammatory mediators in lung epithelial fluid which
