Dexamethasone induces apoptosis in pulmonary arterial smooth muscle
cells
cells
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
Dexamethasone suppressed inflammation and haemodynamic changes in
an animal model of pulmonary arterial hypertension (PAH). A major
target for dexamethasone actions is NFκB, which is activated in
pulmonary vascular cells and perivascular inflammatory cells in PAH.
Reverse remodelling is an important concept in PAH disease therapy,
and further to its antiproliferative effects, we sought to explore whether
dexamethasone augments pulmonary arterial smooth muscle cell
(PASMC) apoptosis.
Methods
Analysis of apoptosis markers (caspase 3, insitu DNA fragmentation)
and NFκB (p65 and phosphoIKKα/β) activation was performed on
lung tissue from rats with monocrotaline (MCT)induced pulmonary
hypertension (PH), before and after day 14–28 treatment with
dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH
model and from normal human lung following lung cancer surgery.
Following stimulation with TNFα (10 ng/ml), the effects of
dexamethasone (10 –10 M) and IKK2 (NFκB) inhibition
1
2
3
4
5
−8 −6
−6
26/08/2015 e.Proofing
http://eproofing.springer.com/journals/printpage.php?token=z1f6oNo2TW2b02e3UtS87S7AQ0qS0Cpd07hxhERYg8 3/38
(AS602868, 0–3 μM (03×10 M) on IL6 and CXCL8 release and
apoptosis was determined by ELISA and by Hoechst staining. NFκB
activation was measured by TransAm assay.
Results
Dexamethasone treatment of rats with MCTinduced PH in vivo led to
PASMC apoptosis as displayed by increased caspase 3 expression and
DNA fragmentation. A similar effect was seen in vitro using TNFα
simulated human and rat PASMC following both dexamethasone and
IKK2 inhibition. Increased apoptosis was associated with a reduction in
NFκB activation and in IL6 and CXCL8 release from PASMC.
Conclusions
Dexamethasone exerted reverseremodelling effects by augmenting
apoptosis and reversing inflammation in PASMC possibly via inhibition
of NFκB. Future PAH therapies may involve targeting these important
inflammatory pathways.
Dexamethasone suppressed inflammation and haemodynamic changes in
an animal model of pulmonary arterial hypertension (PAH). A major
target for dexamethasone actions is NFκB, which is activated in
pulmonary vascular cells and perivascular inflammatory cells in PAH.
Reverse remodelling is an important concept in PAH disease therapy,
and further to its antiproliferative effects, we sought to explore whether
dexamethasone augments pulmonary arterial smooth muscle cell
(PASMC) apoptosis.
Methods
Analysis of apoptosis markers (caspase 3, insitu DNA fragmentation)
and NFκB (p65 and phosphoIKKα/β) activation was performed on
lung tissue from rats with monocrotaline (MCT)induced pulmonary
hypertension (PH), before and after day 14–28 treatment with
dexamethasone (5 mg/kg/day). PASMC were cultured from this rat PH
model and from normal human lung following lung cancer surgery.
Following stimulation with TNFα (10 ng/ml), the effects of
dexamethasone (10 –10 M) and IKK2 (NFκB) inhibition
1
2
3
4
5
−8 −6
−6
26/08/2015 e.Proofing
http://eproofing.springer.com/journals/printpage.php?token=z1f6oNo2TW2b02e3UtS87S7AQ0qS0Cpd07hxhERYg8 3/38
(AS602868, 0–3 μM (03×10 M) on IL6 and CXCL8 release and
apoptosis was determined by ELISA and by Hoechst staining. NFκB
activation was measured by TransAm assay.
Results
Dexamethasone treatment of rats with MCTinduced PH in vivo led to
PASMC apoptosis as displayed by increased caspase 3 expression and
DNA fragmentation. A similar effect was seen in vitro using TNFα
simulated human and rat PASMC following both dexamethasone and
IKK2 inhibition. Increased apoptosis was associated with a reduction in
NFκB activation and in IL6 and CXCL8 release from PASMC.
Conclusions
Dexamethasone exerted reverseremodelling effects by augmenting
apoptosis and reversing inflammation in PASMC possibly via inhibition
of NFκB. Future PAH therapies may involve targeting these important
inflammatory pathways.
Date Issued
2015-09-18
Date Acceptance
2015-08-18
Citation
Respiratory Research, 2015, 16 (114)
ISSN
1465-993X
Publisher
BioMed Central
Journal / Book Title
Respiratory Research
Volume
16
Issue
114
Copyright Statement
© 2015 Price et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
License URL
Publication Status
Published