Biomedical Engineering Reference
In-Depth Information
than other white blood cell types (82). The corticosteroids beclomethasone,
budesonide, dexamethasone, fluticasone propionate, hydrocortisone, and
prednisolone inhibit apoptosis in a concentration-dependent manner as
assessed by flow cytometric analysis, annexin-V binding, and morphological
analysis (83). The maximal inhibition of apoptosis was 50-60%. This is in
contrast to T cells and eosinophils, where steroids induce apoptosis
(84,85). Moreover, glucocorticoids slightly enhance the inhibitory effect of
GM-CSF on neutrophil apoptosis. This indicates that corticosteroids pro-
long human neutrophil survival by inhibiting apoptosis at clinically relevant
drug concentrations via an effect on GR.
The mechanisms by which human T cell, eosinophil, and neutrophil
apoptotic responses to glucocorticoids differ are unknown. The ratio of
GR
b
to GR
a
has been reported to be 73-fold greater in neutrophils than
in PBMCs (86). This reflects differences observed in relative abundance of
the mRNAs. GR
a
=
GR
b
heterodimers have only 15-20% of the transactivat-
ing activity of GR
a
homodimers. In these studies, the prosurvival activity of
dexamethasone is associated with elevated GR
b
in freshly isolated neutro-
phils, perhaps through formation of GR
a
=
GR
b
heterodimers.
Formation of 52 and 30 kD GR fragments due to proteolysis by neu-
trophil elastase (a 28 kD serine protease) is found in cytosol of leukemia cells
(87). Receptor fragmentation in the cytosol is inhibited by methoxysuccinyl-
alanyl-alanyl-prolyl-valyl-chloromethylketone, a highly specific inhibitor of
neutrophil elastase. The addition of as few as 5% neutrophils to a lymphoid
cell suspension provides sufficient elastase to produce receptor fragmentation.
E.
Latent Viral Infection
Epidemiologic studies have implicated childhood respiratory infection as an
independent risk factor for the subsequent development of persistent asthma
and COPD (88). Excess amounts of adenoviral E1A DNA have been
described in patients with COPD (89) with the ElA protein expressed in
the epithelial cells lining the bronchi, the bronchial glands, gland ducts,
the cells lining the bronchioles, and the type 2 cells lining the alveolar sur-
face (90). ElA-transfected airway epithelial cells after LPS exposure produce
an excess amount of IL-8 and intercellular adhesion molecule (ICAM)-l.
Latent adenovirus infection reduces the inhibitory effects of glucocorticoids
on airway inflammation in ovalbumin-sensitized guinea pigs (91). The
mechanism is not yet fully understood though excessive AP-1 induced by
adenovirus infection may be involved in steroid resistance (92). Thus, ade-
noviruses appear to persist as latent infection in the airways of patients with
COPD and adenoviral E1A proteins capable of activating host transcription
factors and amplifying host gene expression, including those involved in
cigarette smoke-induced lung inflammation and COPD may contribute to
steroid insensitivity in COPD.
