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.
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom; colinchurch@nhs.net.
authors.forename: Alistair C
authors.initials: AC
authors.lastname: Church
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Damien H
authors.initials: DH
authors.lastname: Martin
authors.affiliation: Department of Cardiovascular Biology, University of Strathclyde, Glasgow, United Kingdom;
authors.forename: Roger
authors.initials: R
authors.lastname: Wadsworth
authors.affiliation: Department of Pathology, Southern General Hospital, Glasgow, United Kingdom; and.
authors.forename: Gareth
authors.initials: G
authors.lastname: Bryson
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Fisher
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom;
authors.forename: David J
authors.initials: DJ
authors.lastname: Welsh
authors.affiliation: Scottish Pulmonary Vascular Unit, University of Glasgow, Glasgow, United Kingdom;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Peacock
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; D007093:Imidazoles; D015850:Interleukin-6; D011725:Pyridines; D048308:Mitogen-Activated Protein Kinase 14; C093642:SB 203580
keywords: p38 MAPK; pulmonary hypertension