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The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension
Alistair C. Church, Damien H. Martin, Roger Wadsworth, Gareth Bryson, Andrew J. Fisher, David J. Welsh*, Andrew J. Peacock
The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.
American Journal of Physiology: Lung Cellular and Molecular Physiology
https://doi.org/10.1152/ajplung.00038.2015
Published - 15 Aug 2015
Anti-Inflammatory Agents/pharmacology
Cell Hypoxia
Fibroblasts/drug effects
Hypertension, Pulmonary/drug therapy
Imidazoles/pharmacology
Interleukin-6/metabolism
Mitogen-Activated Protein Kinase 14/antagonists & inhibitors
Pulmonary Artery/drug effects
Pyridines/pharmacology
Rats, Sprague-Dawley
Vascular Remodeling/drug effects
10.1152/ajplung.00038.2015
http://eprints.gla.ac.uk/154520/
Dive into the research topics of 'The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension'. Together they form a unique fingerprint.
Vascular Remodeling Medicine & Life Sciences 100%
p38 Mitogen-Activated Protein Kinases Medicine & Life Sciences 87%
Pulmonary Hypertension Medicine & Life Sciences 84%
Vascular Diseases Medicine & Life Sciences 27%
Rodent Diseases Medicine & Life Sciences 15%
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Biological and Biomedical Sciences - Reader
Church, A. C., Martin, D. H., Wadsworth, R., Bryson, G., Fisher, A. J., Welsh, D. J., & Peacock, A. J. (2015). The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension. American Journal of Physiology: Lung Cellular and Molecular Physiology, 309(4), 333-347. https://doi.org/10.1152/ajplung.00038.2015
Church, Alistair C. ; Martin, Damien H. ; Wadsworth, Roger et al. / The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension. In: American Journal of Physiology: Lung Cellular and Molecular Physiology. 2015 ; Vol. 309, No. 4. pp. 333-347.
@article{3da0f90acb664f3eb8951ffbe2b5f464,
title = "The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension",
abstract = "The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.",
keywords = "Animals, Anti-Inflammatory Agents/pharmacology, Cell Hypoxia, Cell Proliferation, Female, Fibroblasts/drug effects, Humans, Hypertension, Pulmonary/drug therapy, Imidazoles/pharmacology, Interleukin-6/metabolism, Male, Mitogen-Activated Protein Kinase 14/antagonists & inhibitors, Pulmonary Artery/drug effects, Pyridines/pharmacology, Rats, Sprague-Dawley, Vascular Remodeling/drug effects",
author = "Church, {Alistair C.} and Martin, {Damien H.} and Roger Wadsworth and Gareth Bryson and Fisher, {Andrew J.} and Welsh, {David J.} and Peacock, {Andrew J.}",
note = "From Enlighten Acceptance from webpage 13.05.20 EKT",
doi = "10.1152/ajplung.00038.2015",
journal = "American Journal of Physiology: Lung Cellular and Molecular Physiology",
publisher = "American Physiological Society ",
Church, AC, Martin, DH, Wadsworth, R, Bryson, G, Fisher, AJ, Welsh, DJ & Peacock, AJ 2015, 'The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension', American Journal of Physiology: Lung Cellular and Molecular Physiology, vol. 309, no. 4, pp. 333-347. https://doi.org/10.1152/ajplung.00038.2015
The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension. / Church, Alistair C.; Martin, Damien H.; Wadsworth, Roger et al.
In: American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol. 309, No. 4, 15.08.2015, p. 333-347.
T1 - The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension
AU - Church, Alistair C.
AU - Martin, Damien H.
AU - Wadsworth, Roger
AU - Bryson, Gareth
AU - Fisher, Andrew J.
AU - Welsh, David J.
AU - Peacock, Andrew J.
N1 - From Enlighten Acceptance from webpage 13.05.20 EKT
N2 - The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.
AB - The p38 mitogen-activated protein kinase (MAPK) system is increasingly recognized as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Previous in vitro studies suggest p38 MAPKα is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodeling (PVremod). In this study the role of the p38 MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Pharmacological inhibition of p38 MAPKα in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore, with the use of a novel and clinically available p38 MAPKα antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKα was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in the PVremod A reduction of IL-6 levels in serum and lung tissue was found in the drug-treated animals, suggesting a potential mechanism for this reversal in PVremod. This study suggests that the p38 MAPK and the α-isoform plays a pathogenic role in both human disease and rodent models of pulmonary hypertension potentially mediated through IL-6. Selective inhibition of this pathway may provide a novel therapeutic approach that targets both remodeling and inflammatory pathways in pulmonary vascular disease.
KW - Anti-Inflammatory Agents/pharmacology
KW - Cell Hypoxia
KW - Cell Proliferation
KW - Fibroblasts/drug effects
KW - Hypertension, Pulmonary/drug therapy
KW - Imidazoles/pharmacology
KW - Interleukin-6/metabolism
KW - Mitogen-Activated Protein Kinase 14/antagonists & inhibitors
KW - Pulmonary Artery/drug effects
KW - Pyridines/pharmacology
KW - Rats, Sprague-Dawley
KW - Vascular Remodeling/drug effects
U2 - 10.1152/ajplung.00038.2015
DO - 10.1152/ajplung.00038.2015
JO - American Journal of Physiology: Lung Cellular and Molecular Physiology
JF - American Journal of Physiology: Lung Cellular and Molecular Physiology
Church AC, Martin DH, Wadsworth R, Bryson G, Fisher AJ, Welsh DJ et al. The reversal of pulmonary vascular remodeling through inhibition of p38 MAPK-alpha: a potential novel anti-inflammatory strategy in pulmonary hypertension. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2015 Aug 15;309(4):333-347. doi: 10.1152/ajplung.00038.2015
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