Biomedical Engineering Reference
In-Depth Information
dexamethasone and with antisense oligonucleotides directed against c-fos
increased GR-GRE binding to similar levels seen in CS individuals. These
findings suggested that increased c-Fos under basal conditions is the predo-
minant inhibitory activity on GR-DNA binding in CR asthma. In addition,
excessive and constitutive epithelial activation of NF-
k
B and AP-1 in steroid-
resistant Crohn's disease has also been demonstrated (69). Oxidative stress,
such as cigarette smoke and H
2
O
2
, enhances AP-1 and NF-
k
B activation
(70-75). In COPD patients or smokers, NF-
k
B and AP-1 are activated exces-
sively and constitutively, probably by TNF
a
and other proinflammatory
cytokines (11,12).
A marked increase in the expression of activated phosphorylated
c-Jun, enhanced expression of JNK, and greater upregulation of c-Fos
expression is found in the CR compared with the CS asthmatics (76). Corti-
costeroid resistance is strongly associated with perinuclear expression of
active JNK and p38 activation in nucleus of epithelial cells in CR Crohn's
disease (69).
The data to date suggest that increased levels of c-Fos and increased
activation of c-Jun in patients with CR asthma accounts for the increased
AP-1 activity seen in vitro and probably relates to increased activation of
JNK in these subjects. Jun N-terminal kinase regulates the expression and
activation of both major components of AP-1. Elevated JNK activity could
be critical to the mechanisms of steroid-resistant patients and failure to inhi-
bit JNK phosphorylation by glucocorticoids may be a major cause for the
lack of response to glucocorticoids in CR asthma. In addition, excessive
and constitutive epithelial activation of JNK and p38 may in turn suppress
GR function resulting in a feed-forward loop of increasing inflammation
and reduced corticosteroid responsiveness in these patients (69). As oxida-
tive stresses, such as hydrogen peroxide, induce JNK activation and phos-
phorylation, elevated JNK activity may be involved in the mechanism of
steroid insensitivity in COPD (77,78).
Immunoprecipitation experiments have shown that phosphorylated
STAT5 and the GR form immune complexes. This association might lead
to retardation of GR nuclear translocation because IL-2 is not able to
induce steroid insensitivity in splenocytes from STATS knockout mice. This
study demonstrates a novel role for STATS in IL-2-induced steroid sensitiv-
ity (2). Oxidative stress (H
2
O
2
) also stimulates STAT5 activation and consti-
tutive and excessive expression of STATS by oxidative stress (79) might also
be involved in steroid resistance in COPD.
D. Neutrophilic Inflammation
Neutrophils have been implicated in the pathogenesis of many diseases,
including COPD, severe asthma, psoriasis, and a variety of collagen-
vascular diseases (6,80,81). These cells are less sensitive to glucocorticoids
