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Cell signalling and cell responses in pulmonary vascular disease
S155 The role of ST2 in a model of pulmonary hypertension
  1. A Mahmood1,
  2. C McSharry2,
  3. D Xu2,
  4. A J Peacock1,
  5. D J Welsh1
  1. 1Scottish Pulmonary Vascular Unit, Western Infirmary, Glasgow, UK
  2. 2Dept of Immunology, University of Glasgow, Glasgow, UK

Abstract

Background Pulmonary arterial hypertension (PAH) is a fatal condition involving remodelling of the pulmonary vessel wall leading to elevated pulmonary arterial pressure and eventually right heart failure. ST2 is a transmembrane receptor with ligand interleukin-33 (IL-33). p38 MAP kinase is an intracellular signalling molecule shown to be involved in the vascular remodelling associated with PAH; and is also involved in ST2/IL-33 signalling. ST2/IL-33 signalling has been shown to reduce fibrosis in the heart following pressure overload in animal models.

Aims To determine whether ST2/IL-33 signalling was involved in the proliferation of mouse pulmonary artery fibroblasts and if p38 MAP kinase was involved.

Methods Two cell types were used—wild type (WT) and ST2 knockout (ST2−/−) mouse pulmonary artery fibroblasts. Proliferation was assessed by [3H] Thymidine incorporation. Expression of p38 MAP kinase was detected by Western blotting. Cells were cultured at various serum concentrations in normoxia and hypoxia. A p38 MAP kinase inhibitor (SB203580) was used to assess its role in cell proliferation. The effect of IL-33 on cell proliferation and expression of p38 MAP kinase was studied.

Results WT and ST2−/− cells proliferated in response to increasing serum concentration. WT cells hyperproliferated in response to hypoxia. ST2−/− cells hyperproliferated in normoxia and hypoxia compared to WT cells. The hyperproliferation of ST2−/− cells in normoxia and hypoxia could be reduced by p38 MAP kinase inhibition (p38) (see Abstract S155 Figure 1). Phosphorylated p38 MAP kinase was detected in all ST2−/− cells and in WT cells in hypoxia with 10% serum, demonstrating p38 MAP kinase is involved in the hyperproliferation observed. Hyperproliferation in response to hypoxia in WT cells could be blocked by addition of IL-33. IL-33 stimulation also decreased the phosphorylation of p38 MAP kinase. There was no effect of IL-33 on ST2−/− cells.

Abstract S155 Figure 1

Proliferation in Response to pp38 MAP Kinase Inhibition in Normoxia ST2-/- cells were cultured in normoxia at serum concentrations 0, 0.3, 1, 3, 5 and 10%, with and without the p38 MAP kinase inhibitor SB203580. Proliferation was reduced in the presence of the inhibitor with statistical significance at serum concentrations ?1% serum suggesting that p38 MAP kinase is involved in the hyperproliferation seen in ST2-/- cells.

Conclusions Mouse pulmonary artery fibroblasts hyperproliferate in response to hypoxia and in the absence of the ST2 receptor. This hyperproliferation involves phosphorylation of p38 MAP kinase. This phosphorylation and excessive cell proliferation can be blocked by ST2/IL-33 signalling. ST2 may be a potentially novel therapeutic target in the PAH.

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