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The role of oxygen sensing pathways in infection and inflammation.

Thompson, A. A. Roger (2012) The role of oxygen sensing pathways in infection and inflammation. PhD thesis, University of Sheffield.

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Many inflammatory diseases are characterised by persistent and inappropriate neutrophil activation, systemic or localised hypoxia and bacterial colonisation. Hypoxia represents an important regulator of inflammatory responses since it inhibits neutrophil apoptosis, a process central to timely resolution of inflammation. Furthermore, the oxygen sensing transcription factor, HIF-1α is a critical regulator of myeloid cell function and neutrophil survival in hypoxia. I show that HIF-2α has a distinct role from HIF-1α in regulating survival of inflammatory neutrophils. Specifically, HIF-2α was expressed in neutrophils from patients with chronic inflammatory diseases and was upregulated by inflammatory stimuli and in a mouse model of acute lung inflammation. Overexpression of HIF-2α inhibited constitutive apoptosis of human neutrophils in vitro and delayed resolution of inflammation in an in vivo model of zebrafish tailfin injury. By contrast, myeloid-specific deficiency of HIF-2α enhanced resolution of inflammation in a murine model of lung inflammation but did not impair essential neutrophil antimicrobial functions in vitro or in vivo. These findings implicate HIF-2α as a potential target for treating neutrophilic inflammation. Infections frequently cause or complicate illnesses associated with arterial hypoxaemia and local tissue hypoxia. I investigated the effect of systemic hypoxia on host-pathogen interactions using a subcutaneous infection model in mice. Surprisingly ambient hypoxia transformed the local bacterial challenge into a phenotype of sickness behaviour and hypothermia. The mechanism responsible for this phenotype was not discovered but I found no evidence of bacteraemia, excessive cytokine production or lung injury in the hypoxic infected mice. However, there was significant circulatory dysfunction, with hypotension, bradycardia and impaired left ventricular function. These findings imply that hypoxia may adversely alter the host response to a minor bacterial challenge, leading to profound systemic illness. Interestingly, myeloid-cell deficiency of HIF-2α protected mice from the adverse systemic phenotype in this model, further supporting the potential utility of targeting HIF-2α in inflammatory disease.

Item Type: Thesis (PhD)
Keywords: Hypoxia, Neutrophil, Inflammation, Staphylococcus, Hypoxia inducible factor
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: Dr A. A. Roger Thompson
Date Deposited: 13 Nov 2012 12:56
Last Modified: 08 Aug 2013 08:50
URI: http://etheses.whiterose.ac.uk/id/eprint/2888

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