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Title: Sepsis in pregnancy : a rodent model exploring the cardiovascular adaptation and susceptibility to infection
Author: Zöllner, Julia
ISNI:       0000 0004 7963 6975
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Sepsis is a major cause of maternal mortality worldwide and is therefore an area of particular importance. Septic shock is characterised by cardiovascular collapse and multi organ dysfunction resulting from an overwhelming immune response to a bacterial infection. Nitric oxide (NO) release during pregnancy may exacerbate sepsis-induced hypotension. The endogenous inhibitor of nitric oxide synthase, asymmetric dimethylarginine (ADMA), is an important regulator of vascular NO production in sepsis. DDAH1 (Dimethylargnine Dimethylamino Hydrolase) regulates ADMA concentrations in the vasculature. The objective of this thesis was to understand the impact of sepsis on cardiovascular function during pregnancy using a polymicrobial sepsis model in rodents. In addition, the impact of treatment with L-257, a DDAH1-selective inhibitor on maternal outcomes during septic shock in pregnancy was investigated. Mortality was significantly increased during pregnancy as compared to non-pregnant controls (10% vs 50%). Cardiovascular collapse ensued in the 24 hours preceding the humane endpoint in both groups and was comparable. The cytokine and chemokine response during pregnancy did not demonstrate an immunocompromised phenotype or Th1/Th2 bias. Leukocyte trafficking to lung was increased during pregnancy and appeared to be exaggerated as compared to non-pregnant controls. Bacterial load in blood and peritoneal fluid was not increased during pregnancy and nor were NO levels elevated. DDAH1 inhibition appeared to be valuable during sepsis in pregnancy. Findings indicated that treatment with L-257 and Imipenem treatment improved haemodynamic function, decreased the bacterial load and consequently improved survival in experimental septic shock to 50%. DDAH1 inhibition provided cardiovascular support without impairing the pathogen-specific immune response. Aortic cell lysate showed increased ADMA concentration following L-257 treatment. Therefore, DDAH1 inhibition may offer a new therapeutic pathway for pregnant women with septic shock and may result in better outcomes for both mothers and babies.
Supervisor: Johnson, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral