White Rose University Consortium logo
University of Leeds logo University of Sheffield logo York University logo

Links between dysfunctional Bone Morphogenetic Protein signalling and Interleukin-1ß mediated inflammation in pulmonary arterial hypertension

Pickworth, Josephine (2017) Links between dysfunctional Bone Morphogenetic Protein signalling and Interleukin-1ß mediated inflammation in pulmonary arterial hypertension. PhD thesis, University of Sheffield.

[img] Text (J Pickworth PhD thesis)
JP corrected Thesis final for white rose.docx
Available under License Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 UK: England & Wales.

Download (31Mb)

Abstract

Rationale: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in up to 70% of patients with heritable and up to 25% with idiopathic pulmonary arterial hypertension, however penetrance within families with the same mutation is low implying the necessity for a ‘second hit’. Inflammatory cytokines are raised in patients with PAH, and in animal models have been shown to play a modulating role in disease pathogenesis. Objective: To determine whether there is a pulmonary specific interplay between BMPR2 deficiency and inflammatory Interleukin 1ß (IL-1ß) signalling that may explain the local manifestation of PAH in the lung. Methods and Results: mRNA microarray analysis of RNA isolated from pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells demonstrated reduced inflammatory pathway activation in response to IL-1ß in PASMC compared with AoSMCs. However, further microarray analysis of PASMCs analysis demonstrated an exaggerated inflammatory response to IL-1ß upon loss of BMPR2 signalling. To determine whether IL-1ß supplementation would exacerbate disease phenotype on the background of a BMPR2 mutation, R899X+/- BMPR2 transgenic mice fed western diet for six weeks were given daily injections of IL-1ß. IL-1ß treated mice had higher white blood cell counts, demonstrating effective administration of IL-1ß. Raised serum protein levels of Interleukin-6 and Osteoprotegerin recapitulating in vitro PASMC data. Phenotypically, IL-1ß treated mice demonstrated a significant increase in pulmonary vascular remodelling. Conclusion: IL-1ß induces a pulmonary artery-specific transcriptome that is altered by suppression of BMPR2 signalling in vitro. In vivo and in vitro IL-1ß drives an exaggerated inflammatory response under conditions where BMPR2 signalling is reduced.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.727302
Depositing User: Mrs Josephine Pickworth
Date Deposited: 13 Nov 2017 10:40
Last Modified: 12 Oct 2018 09:47
URI: http://etheses.whiterose.ac.uk/id/eprint/18607

You do not need to contact us to get a copy of this thesis. Please use the 'Download' link(s) above to get a copy.
You can contact us about this thesis. If you need to make a general enquiry, please see the Contact us page.

Actions (repository staff only: login required)