Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.634082
Title: Inflammation in pulmonary arterial hypertension : NF-kappa B signalling and the role of corticosteroids
Author: Price, Laura
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Abstract:
Pulmonary arterial hypertension (PAH) is a severe disease with limited therapeutic options characterised by proliferation of vascular cells, which in part relates to the presence of increased inflammation. I hypothesised that the inflammatory transcription factor NF-kappa B (NF-κB) was activated in human idiopathic PAH (iPAH), and that inhibition of NF­‐κB using the synthetic glucocorticoid (GC) dexamethasone would reverse pulmonary hypertension (PH) and inflammation in the rat monocrotaline (MCT) model; in rat and human pulmonary arterial smooth muscle cells (PASMC); and in human peripheral blood mononuclear cells (PBMC). Activation of NF-κB was demonstrated in pulmonary macrophages, lymphocytes, pulmonary endothelial cells (EC) and PASMC in patients with severe iPAH, and in the rat MCT model. Dexamethasone reversed PH and improved survival in MCT-induced PH in rats, with a reduction in interleukin (IL)-6 expression, and a reduction in vascular cell NF-κB activation. Pulmonary BMPR­‐II mRNA expression was also low in rats with MCT-PH; this was increased following dexamethasone treatment. The dexamethasone-induced reduction in rat vessel medial thickness was related to both a reduction in serum-stimulated rat PASMC proliferation, and also increased PASMC apoptosis. I then demonstrated that dexamethasone inhibited lipopolysaccharide (LPS)- and TNF-α-induced IL-6 and CXCL8 release in an NF-κB-dependent manner in control human PASMC, whole blood and PBMC assays. When stimulated with these activators of NF-κB, PBMC from PAH patients were relatively hyporesponsive compared to control cells in terms of IL-6 and CXCL8 release, and were less responsive i.e. more resistant to dexamethasone‐induced suppression of cytokine release compared to controls. NF-κB activation is marked in patients with end-stage iPAH, and reversal of NF-κB activation and PH is possible in the MCT-induced PH model. Whether inflammation might be a therapeutic target in human PAH - and whether PAH is a clinically GC-sensitive or GC-resistant condition - requires further exploration.
Supervisor: Wort, John ; Adcock, Ian ; Howard, Luke Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.634082  DOI: Not available
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