Background: The p38 Mitogen Activated Protein Kinase (MAPK) system is increasingly recognised as an important inflammatory pathway in systemic vascular disease but its role in pulmonary vascular disease is unclear. Indeed, Inflammation is becoming increasingly recognised as driving the process of pulmonary vascular remodelling. Previous in vitro studies suggest p38MAPKa is critical in the proliferation of pulmonary artery fibroblasts, an important step in the pathogenesis of pulmonary vascular remodelling. In this study the role of the p38MAPK pathway was investigated in both in vitro and in vivo models of pulmonary hypertension and human disease. Aims: To investigate the role that the pro-inflammatory pathway mediated by p38MAPK and the alpha isoform in particular, might have in pulmonary hypertension and whether manipulation might offer a mechanism for reversal of pulmonary vascular remodelling. Methods and results: Pharmacological inhibition of p38MAPKa in both chronic hypoxic and monocrotaline rodent models of pulmonary hypertension prevented and reversed the pulmonary hypertensive phenotype. Furthermore by using a novel and clinically available p38MAPKa antagonist, reversal of pulmonary hypertension was obtained in both experimental models. Increased expression of phosphorylated p38MAPK and p38MAPK was observed in the pulmonary vasculature from patients with idiopathic pulmonary arterial hypertension, suggesting a role for activation of this pathway in pulmonary vascular remodelling. A reduction of IL-6 levels in both serum and lung tissue was found in the drug treated animals, suggesting a link between p38MAPK and the inflammatory pathway in pulmonary hypertension. Furthermore a reduction in the amount of soluble collagen was also observed in the drug treated animals. In vitro work has shown that the pulmonary artery fibroblast is an important source of both inflammatory mediators and collagen, released through a p38MAPK dependent system, and that this cell may be essential in the propagation of vascular remodelling. Conclusions: This study suggests that the p38 MAPK pathway 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 remodelling and inflammatory pathways in pulmonary vascular disease.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634006 |
| Date | January 2015 |
| Creators | Church, Alistair Colin |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/5874/ |
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