The p38 MAPK pathway is increasingly recognised as important in inflammation leading to systemic vascular disease but its role in pulmonary vascular disease is unclear. Our group has previously identified the p38MAPKα isoform to be critical in hypoxic-induced proliferation of pulmonary artery fibroblasts, a key step in the pathogenesis of pulmonary vascular remodelling. This study sought to investigate the role of p38MAPK in animal models of pulmonary hypertension and in human disease.
Methods Sprague Dawley rats were exposed to chronic hypoxia for 14 days and received a selective p38 MAPKα inhibitor from day 1 in a prevention strategy, or after 14 days in a treatment strategy. Both prevention and treatment methods were further employed in a second monocrotaline animal model. Haemodynamic measurements (right ventricular systolic pressure RVSP, right ventricular hypertrophy RVH) were performed, and lungs were removed for immunohistochemistry (IHC) and biochemical analysis. Multiplex ELISA was used to analyse cytokine profile in rat serum. Primary PAF were isolated and siRNA techniques employed to knockdown p38MAPKα. IHC for p38 MAPKα was performed on human tissue from patients with idiopathic pulmonary arterial hypertension.
Results siRNA to p38MAPKα inhibited the hypoxic induced proliferation of PAFs. Increased levels of total p38 MAPK activity and increased expression of the alpha isoform was found in the lungs of both chronic hypoxic and MCT animals compared to normal. Using the p38 MAPK inhibitor in the chronic hypoxic and monocrotaline in vivo prevention study resulted in lower RVSP and RVH in the drug treated animals (p<0.005). In the reversal study of both animal models the inhibitor reversed established pulmonary hypertension as determined by RVSP and RVH (p<0.001). Both serum and whole lung levels of IL-6 were lower in the drug treated animals compared to normal. Increased expression of p38 MAPK was observed in lungs from IPAH patients compared to control.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.