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Title: Investigating the role of inflammation and the HIF pathway in pulmonary arterial hypertension
Author: Parmar, Selina
ISNI:       0000 0004 2744 1105
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2013
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Pulmonary arterial hypertension (PAH) is a potentially devastating disease characterised by the occlusion and narrowing of the pulmonary arteries, leading to increased vascular resistance and right ventricular pressure and eventual right heart failure. Diseased vessels have been shown to have a dramatically thickened medial layer and lesions characteristic to pulmonary hypertension display excessive SMC deposition. Much work has been done to try and understand the structural pathogenesis of the disease but it is still little understood what is driving the vascular remodelling process. Inflammatory cells are thought to have a role and there is evidence of immune cell infiltrates in diseased vessels in both animal models of PAH and in PAH patient lung sections. Within these immune cell infiltrates, the monocyte is of particular interest. Monocytes have been shown to be present in a variety of animal models of PH and have been shown to be actively entering pulmonary vessels in rats prior to the development of monocrotaline (MCT) induced PH. Also monocytes have been found in plexiform lesions of pulmonary arteries isolated from children with the sporadic form of the disease but not in left heart disease associated forms of pulmonary hypertension. Moreover, with systemic proinflammatory cytokine expression found to be altered in PAH and monocytes being a major source of cytokines, the monocyte is a very interesting cell type to study in relation to PAH. Interestingly, the hypoxia inducible transcription factor, HIF, has also been found within diseased vessels. HIF is essential for myeloid cell function therefore perhaps there is a related role of the monocytes and HIF in the remodelled vessels. HIF can also be an indirect indicator of hypoxia, although the exact oxygen tensions of these areas are yet to be established. The effect of hypoxia on SMCs is controversial but there is a body of data suggesting that hypoxia induces SMC proliferation. Therefore my hypothesis is that hypoxia can induce SMC proliferation which monocytes can alter via the HIF pathway and this is different in PAH.
Supervisor: Walmsley, Sarah ; Whyte, Moira Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available