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Title: Understanding the link between amino acids and vascular function in cardiovascular inflammation and sepsis
Author: Tesfai, Abel
ISNI:       0000 0004 7655 5993
Awarding Body: University of London
Current Institution: Imperial College London
Date of Award: 2018
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Sepsis is a ‘life-threatening disease caused by a dysregulated host response to an infection’. Despite advancements, effective treatments and biomarkers have remained elusive. However, nitric oxide (NO) and related pathways are emerging as biomarkers/targets. NO levels are driven by amino acids, which cycle to regulate NO synthase (NOS) substrate L-arginine and inhibitors including asymmetric dimethylarginine (ADMA). Furthermore, the consequence of changes of plasma amine-constituents in sepsis, on NOS activity ex vivo is not known. Thus, in this thesis I used a well-defined clinical cohort to address the influence of sepsis on (i) the amine metabolome, (ii) the ability of plasma to ‘support’ NOS activity in a simple mouse cell bioassay and (iii) plasma amine-constituents and correlations to clinical outcome measures. The main results reported within this thesis include: (i) LPS-activated mouse macrophages provided a viable bioassay platform to test ‘NOS supporting activity’ in the presence of 100% human plasma. In sepsis, ‘NOS supporting activity’ of plasma was reduced, which corresponded to an increased ADMA:L-arginine ratio. Both ADMA and ADMA:L-arginine ratio also positively correlated to clinical scores of sepsis. Similarly, the ADMA:L-arginine ratio was increased in an in vivo mouse model of sepsis but unlike in humans this was driven entirely by reduced L-arginine. (ii) Analysis of gene expression in spleen and kidney tissues from LPS-treated mice revealed a complex interplay between pathways that utilise L-arginine and that generate/metabolise methylarginines. (iii) Using a novel ultra-high-performance mass spectrometry platform, 34 human plasma amines were quantified from sepsis patients, of which 21 amines were significantly altered and mapped to both canonical NOS pathways and L-arginine/L-glutamine degradation pathways. Taurine emerged as an important diagnostic (reduced in sepsis) and prognostic (reduced in survivors) indicator. (iv) Using a blood vessel bioassay demonstrated taurine augmented the vasoplegia induced by LPS and interferon.
Supervisor: Mitchell, Jane Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral