AbstractA better understanding of the pathophysiology of sepsis is required to improve current treatments. The bioavailability of two amino acids, arginine and tryptophan, can help regulate both microvascular and immune function. The aim of this thesis was to investigate the role of inflammation and amino acid bioavailability in the pathophysiology of sepsis.
The methodology presented in this thesis shows that HPLC is an effective way to accurately measure amino acids and their metabolites in plasma from sepsis patients. Furthermore, results from a time-course experiment demonstrated that plasma needs to be promptly separated from blood after collection in order to obtain reliable measurements of arginine.
We found that increased circulating neutrophil counts were associated with increased plasma arginase activity, and decreased plasma arginine concentrations in sepsis. Furthermore we found that arginine bioavailability to nitric oxide synthase was further reduced by increased concentrations of asymmetric dimethylarginine in patients with septic shock. The ratio of arginine to asymmetric dimethylarginine was associated with decreased microvascular reactivity and increased inflammation in sepsis.
We found that sepsis patients have decreased plasma tryptophan and increased plasma kynurenine concentrations, suggesting increased indoleamine 2,3- dioxygenase activity. An increased ratio of kynurenine to tryptophan was associated with decreased microvascular reactivity, increased inflammation and circulating T cell lymphopenia.
Finally, we identified circulating activated granulocytes with a myeloid derived suppressor cell phenotype in septic shock patients which impair T cell signalling, partly via arginine depletion. The percentage of myeloid derived suppressor cells in sepsis was directly associated with plasma interleukin-6 concentrations.
In summary, these findings demonstrate that systemic inflammation in sepsis is associated with both decreased amino acid bioavailability and increased circulating myeloid derived suppressor cells. Decreased amino acid bioavailability may contribute to endothelial and immune dysfunction in sepsis. Therapies which improve amino acid bioavailability may be potential adjunctive treatments in sepsis.
|Date of Award||Oct 2010|
|Supervisor||Tonia Woodberry (Supervisor), Nicholas Anstey (Supervisor) & Yvette McNeil (Supervisor)|