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Linking mechanisms to prognosis in pulmonary arterial hypertension
S68 Inhibition of p38 mitogen activated protein kinase (MAPK) prevents the development of experimental pulmonary hypertension
  1. A C Church1,
  2. R Wadsworth1,
  3. G Bryson2,
  4. D J Welsh1,
  5. A J Peacock1
  1. 1Scottish Pulmonary Vascular Unit, Glasgow, UK
  2. 2Department of Pathology, Southern General Hospital, Glasgow, UK

Abstract

Introduction p38 MAPK has been linked to the pathobiology of pulmonary hypertension (PH) but its role has not been fully investigated. We have previously highlighted the importance of the p38 MAPK pathway in the proliferative response of pulmonary artery fibroblasts to hypoxia. In addition, the BMPR2 mutations seen in PH can lead to increased signalling through the p38 MAPK pathway. These findings suggest p38 MAPK may be an appropriate target for the treatment of PH.

Methods We undertook an in vivo prevention study on male Sprague-Dawley rats that were exposed to hypobaric hypoxia (at 550 mm Hg=10% FiO2) for a period of 2 weeks. Five animals were dosed daily via an intraperitoneal route, with SB-203580, a p38 MAPK specific inhibitor, and a further five animals acted as controls. After 2 weeks the animals had right ventricular systolic pressure (RVSP) measured, degree of right ventricular hypertrophy (RVH) assessed and lung histology analysed for evidence of vascular remodelling. The lungs were stained with α-smooth muscle actin and the degree of distal muscularisation in vessels <80 mm in diameter assessed. Results were analysed with appropriate statistical tests.

Results There was a significant difference in the RVSP between groups (control 37.09 mm Hg±5.09 vs drug 20.59 mm Hg ±3.19; p=0.025). There was less RVH (control 0.38 vs drug 0.25;p=0.0032) in the drug treated group (see Abstract S68 figure 1) and the total RV weights were also less (control 147 mg vs drug 109 mg; p=0.018). There was no difference in haematocrit between groups. There was less pulmonary vascular remodelling as indicated by a reduction of fully muscularised and an increase in non-muscularised vessels observed in the drug treated group (p<0.001).

Abstract S68 Figure 1

RV/LV+septum ratio.

Conclusion We have shown in a chronic hypoxic model of PH that by inhibiting the p38 MAPK pathway in vivo the development of pulmonary hypertension can be prevented. This suggests that the p38 MAPK pathway could be a potential therapeutic target for PH. Further studies are warranted, in particular to see if inhibition can reverse established disease.

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