Biomedical Engineering Reference
In-Depth Information
Figure 2
Steroid insensitivity in COPD alveolar macrophages and H
2
O
2
-treated
U937 cells. (A) Interleukin-8 production in alveolar macrophages from healthy non-
smokers and COPD patients. Alveolar macrophages were stimulated with TNF
a
(10 ng
=
mL) with or without 30-min pretreatment of dexamethasone (Dex:
10
6 M). In alveolar macrophages from COPD, dexamethasone was not effective
on TNF
a
-induced IL-8 production. (B) Dose-dependent inhibition of LPS-induced
IL-8 production by Dex in U937 cells. The cells were stimulated with LPS
(500 ng
=
mL) with (triangle) or without (square) 4 hr pretreatment of H
2
O
2
(l00
m
M). Various concentrations of Dex were pretreated for 30 min before LPS
stimulation. H
2
O
2
treatment enhanced IL-8 production and decreased corticosteroid
action. (From Ref. 94.)
from these subjects has been ascribed to a reduced number of GR, altered
affinity of the ligand for GR, reduced ability of the GR to bind to DNA,
or increased expression of inflammatory transcription factors, such as
AP-1, that compete for DNA binding or reduction of HDAC (2,51).
A. Defects in GR Sequence and Pharmacokinetics
Unlike familial corticosteroid resistance, where there is a mutation in the
LBD of GR and a subsequent resetting of the basal cortisol level, CR
asthma patients have normal cortisol levels and are not Addisonian (52).
Plasma morning serum cortisol or 24 hr urinary cortisol excretions reported
to be normal or increased in COPD (53,54). Using standard steroid suppres-
sion tests, CR asthmatics and COPD patients do not have an altered secre-
tory rate of endogenous cortisol or an altered sensitivity of the HPA axis
(55,56). By chemical mutational analysis, no mutations in the GR of CR
patients were observed in CR asthmatics (57). This was confirmed in a later
study, which used RT-PCR and direct sequencing of the GR (58). It is
therefore unlikely that the defect in CR asthmatics and COPD lies in the
structure of the GR.
