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The role of Tumour Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) in Pulmonary Arterial Hypertension.

Hameed, Abdul (2018) The role of Tumour Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL) in Pulmonary Arterial Hypertension. PhD thesis, University of Sheffield.

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Abstract

Background Pulmonary arterial hypertension (PAH) is an obliterative vasculopathy characterized by endothelial and smooth muscle cell proliferation affecting small arterioles resulting in progressive elevation of pressure within the lungs. This poses significant load on the right heart which can lead to heart failure. It is a devastating and life threatening disease as patients are frequently diagnosed at an advanced stage. Existing drug therapies augmenting pulmonary vasodilatation have significantly improved patient morbidity but insufficiently modify vascular remodeling and consequently have modestly improved survival. Halting or reversing vascular remodeling could revolutionise human therapy but has yet to come to fruition. To improve disease prognosis, identifying key disease pathways is a priority for developing newer therapies. A role for Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in regulating endothelial cell and smooth muscle cell physiology has been reported in the systemic vasculature but hitherto unexplored in the pulmonary circulation. I hypothesised that TRAIL is an essential mediator in the pathogenesis of PAH. Methods: Expression of TRAIL in human and rodent PAH and the mitogenic effects of TRAIL on pulmonary artery smooth muscle cells (PASMCs) were characterised. The pathogenic role of TRAIL in three independent rodent models of disease was determined and the efficacy of inhibiting TRAIL in halting or regressing established disease was tested. Phenotyping included cardiac catheterisation, echocardiography, and pulmonary vascular immunohistochemistry. Findings Gene and protein expression of TRAIL ligand and receptors were upregulated in PASMCs from patients with PAH. In-vitro TRAIL was a mitogen for PASMCs. TRAIL-deficient mice were protected from both hypoxia and diet-induced PAH. Antibody blockade prevented rats from developing MCT induced PAH. Bone marrow transplantation in chimeric mice supported a role for tissue derived TRAIL. In mice and rats with established disease, an anti-TRAIL antibody improved pulmonary haemodynamics, reversed pulmonary vascular remodeling, reduced proliferation and increased apoptosis in vascular lesions and significantly improved survival. Conclusion: My preclinical studies are the first to determine the importance of TRAIL in the pathogenesis of experimental pulmonary arterial hypertension and highlight its potential as a novel therapeutic target for directing future therapies.

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.770203
Depositing User: Dr Abdul Hameed
Date Deposited: 01 Apr 2019 08:46
Last Modified: 25 Sep 2019 20:07
URI: http://etheses.whiterose.ac.uk/id/eprint/23433

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