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dc.contributor.advisorWalmsley, Sarahen
dc.contributor.advisorWhyte, Moiraen
dc.contributor.authorDickinson, Rebecca Sallyen
dc.date.accessioned2018-03-15T12:35:42Z
dc.date.available2018-03-15T12:35:42Z
dc.date.issued2017-12-01
dc.identifier.urihttp://hdl.handle.net/1842/28822
dc.description.abstractIntroduction – Severe pulmonary bacterial infections are frequently complicated by systemic hypoxaemia and, in the context of acute respiratory distress syndrome (ARDS), inappropriately prolonged neutrophilic inflammation. This combination of acute hypoxaemia and persistent inflammatory response carries significant morbidity and mortality. However, patients with chronic lung disease function in the community with chronic systemic hypoxaemia and bacterial colonisation with much lower acute mortality. The HIF/PHD pathway tightly regulates neutrophilic responses to hypoxia and bacteria. Here, using acute bacterial pneumonia models, I have dissected the differences in innate immune responses to infection in acute hypoxia and following exposure to hypoxia prior to infection (‘preconditioning’). Methods – C57BL/6 mice were housed in room air or ‘preconditioned’ by exposure to 10% ambient hypoxia for seven days. They were then instilled with intratracheal Streptococcus pneumoniae (1x104 or 1x107 cfu to assess macrophage and neutrophil function respectively) under recovery anaesthesia and housed in normoxia (21% O2) or hypoxia (10% O2). At pre-determined time-points, the animals were assessed clinically for sickness and rectal temperature. Blood, bronchoalveolar lavage and tissues were taken for analysis. Transcriptome analysis by RNA-sequencing and functional glycolysis by Seahorse was performed on blood leucocytes. Results – Concurrent exposure to hypoxia and infection resulted in neutrophil-mediated morbidity and mortality. Acute hypoxia caused rapid utilisation of glucose, glycogen and fat stores resulting in systemic hypoglycaemia and death. Preconditioning with exposure to hypoxia prior to infection completely protected the host against hypoxia-induced morbidity and mortality by suppressing leucocyte glycolysis, through suppression of HIF1α, and resultant rescue from the negative energy state and cardiovascular compromise. Conclusion – Hypoxia preconditions the innate immune response by suppression of HIF1α and glycolysis in leucocytes, thereby protecting against acute hypoxia-induced mortality outcomes in acute bacterial pulmonary infection.en
dc.contributor.sponsorMedical Research Council (MRC)en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionJones, R., McDonald, K. E., Willson, J. A., Ghesquiere, B., Sammut, D., Daniel, E., Harris, A. J., Lewis, A., Thompson, A. A. R., Dickinson, R. S., Plant, T., Murphy, F., Sadiku, P., Keevil, B. G., Carmeliet, P., Whyte, M. K. B., Newell-Price, J. and Walmsley, S. R. (2016) 'Mutations in succinate dehydrogenase B (SDHB) enhance neutrophil survival independent of HIF-1 alpha expression', Blood, 127(21), pp. 2641-2644.en
dc.relation.hasversionThompson, A. A. R., Dickinson, R. S., Murphy, F., Thomson, J. P., Marriott, H. M., Tavares, A., Willson, J., Williams, L., Lewis, A., Mirchandani, A., Dos Santos Coelho, P., Doherty, C., Ryan, E., Watts, E., Morton, N. M., Forbes, S., Stimson, R. H., Hameed, A. G., Arnold, N., Preston, J. A., Lawrie, A., Finisguerra, V., Mazzone, M., Sadiku, P., Goveia, J., Taverna, F., Carmeliet, P., Foster, S. J., Chilvers, E. R., Cowburn, A. S., Dockrell, D. H., Johnson, R. S., Meehan, R. R., Whyte, M. K. B. and Walmsley, S. R. (2017) 'Hypoxia determines survival outcomes of bacterial infection through HIF-1α– dependent reprogramming of leukocyte metabolism', Science Immunology, 2(8).en
dc.subjectneutrophilsen
dc.subjectlow oxygen levelsen
dc.subjecthypoxaemiaen
dc.titleHypoxia and the regulation of host responses to acute bacterial pulmonary infectionsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.rights.embargodate2100-12-31
dcterms.accessRightsRestricted Accessen


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