comunitat-uji-handle:10234/9
comunitat-uji-handle2:10234/36080
comunitat-uji-handle3:10234/36082
comunitat-uji-handle4:
INVESTIGACION
Resum
Background:
Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy
for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. ... [+]
Background:
Inhaled corticosteroid (ICS) with long-acting beta-2 agonists is a well-documented combination therapy
for chronic obstructive pulmonary disease (COPD) based on its additive anti-inflammatory properties. By contrast, the
recommendation of ICS in combination with long-acting muscarinic antagonist (LAMA) is not evidence-based. In this
study, neutrophils obtained from COPD patients were used to compare the anti-inflammatory effects of aclidinium
bromide (a long-acting muscarinic antagonist) with corticosteroids and their potential additive effect.
Methods:
Human sputum and blood neutrophils were isolated from healthy individuals (
n
= 37), patients with stable
COPD (
n
= 52) and those with exacerbated COPD (
n
= 16). The cells were incubated with corticosteroid fluticasone
propionate (0.1 nM
–
1
μ
M), aclidinium bromide (0.1 nM
–
1
μ
M) or a combination thereof and stimulated with 1
μ
gof
lipopolysaccharide/ml or 5 % cigarette smoke extract. Levels of the pro-inflammatory mediators interleukin-8, matrix
metalloproteinase-9, CCL-5, granulocyte-macrophage colony-stimulating factor and interleukin-1
β
were measured and
the mechanisms of corticosteroid resistance evaluated at the end of the incubation.
Results:
The non-neuronal cholinergic system w
as over-expressed in neutrophils fr
om COPD patients, as evidenced by
increases in the expression of muscarinic
receptors (M2, M4 and M5), choline acetyltransferase and vesicular acetylcholine
transporter. Aclidinium bromide demonstrated anti-inflamm
atory effects on neutrophils from COPD patients, reversing
their resistance to corticosteroids. Additive effects of c
ombined aclidinium bromide and fluticasone propionate in
blocking M2 receptor levels, inhibi
ting phosphoinositide 3-kinase-
δ
and enhancing the glucocorticoid response element
transcription factor were demonstrated and were accompanied
by an increase in the corticosteroid-induced expression
of anti-inflammatory-related genes.
Conclusions:
LAMAs potentiate the anti-inflammatory effects of corticosteroids in neutrophils from COPD patients
in vitro, thus providing a scientific rationale for their use in combination with corticosteroids in the treatment of COPD. [-]
Drets d'accés
info:eu-repo/semantics/openAccess