|dc.description.abstract||Introduction – 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.relation.hasversion||Jones, 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.hasversion||Thompson, 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