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.