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

Research output: Contribution to journalArticle

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 MAPKalpha 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 MAPKalpha 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 MAPKalpha antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKalpha 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 alpha-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.
Original languageEnglish
Pages (from-to)L333-L347
JournalAmerican Journal of Physiology: Lung Cellular and Molecular Physiology
Volume309
Issue number4
DOIs
Publication statusPublished - 1 Aug 2015

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p38 Mitogen-Activated Protein Kinases
Pulmonary Hypertension
Anti-Inflammatory Agents
Lung
Vascular Diseases
Lung Diseases
Interleukin-6
Rodent Diseases
Monocrotaline
Pulmonary Artery
Vascular Remodeling
Rodentia
Protein Isoforms
Theoretical Models
Fibroblasts
Pharmacology
Phenotype
Serum
Pharmaceutical Preparations

Cite this

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), L333-L347. https://doi.org/10.1152/ajplung.00038.2015
Church, Alistair C. ; Martin, Damien H. ; Wadsworth, Roger ; Bryson, Gareth ; Fisher, Andrew J. ; Welsh, David J. ; Peacock, Andrew J. / 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. L333-L347.
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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. L333-L347. 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; Bryson, Gareth; Fisher, Andrew J.; Welsh, David J.; Peacock, Andrew J.

In: American Journal of Physiology: Lung Cellular and Molecular Physiology, Vol. 309, No. 4, 01.08.2015, p. L333-L347.

Research output: Contribution to journalArticle

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AU - Church, Alistair C.

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AU - Bryson, Gareth

AU - Fisher, Andrew J.

AU - Welsh, David J.

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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 MAPKalpha 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 MAPKalpha 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 MAPKalpha antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38 MAPK and p38 MAPKalpha 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 alpha-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.

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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 1;309(4):L333-L347. https://doi.org/10.1152/ajplung.00038.2015