An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function

• Published in: PloS one 2011-06, Vol.6 (6), p.e21185
• Main Authors: Darcy, Christabelle J, Davis, Joshua S, Woodberry, Tonia, McNeil, Yvette R, Stephens, Dianne P, Yeo, Tsin W, Anstey, Nicholas M
• Format: Article
• Language: English
• Subjects: Amino acids; Analysis; Apoptosis; Bioavailability; Biological response modifiers; Biology; Blood pressure; Cancer therapies; Catabolism; CD4 antigen; CD8 antigen; Celiac disease; Cell number; Chemistry; Chromatography; Cohort analysis; Cohort Studies; Colonies & territories; Cytokines; Cytokines - blood; Disease; Disease susceptibility; E coli; Endothelial cells; Endothelium; Endothelium, Vascular - physiopathology; Escherichia coli; Female; Granulocytes; Health aspects; Hepatocytes; High performance liquid chromatography; Hospitals; Humans; Immune response; Immunity - immunology; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Infection; Infections; Interferon; Interleukin 10; Interleukins; Kynurenine - blood; Leukocytes; Leukocytes (mononuclear); Liquid chromatography; Lung cancer; Lymphocyte Count; Lymphocytes; Lymphocytes T; Lymphopenia; Male; Medical research; Medicine; Metabolism; Metabolites; Microvasculature; Microvessels - pathology; Microvessels - physiopathology; Middle Aged; Models, Biological; Mortality; Nitric oxide; Nitric-oxide synthase; Observational studies; Preeclampsia; Reactivity; Sepsis; Sepsis - blood; Sepsis - enzymology; Sepsis - immunology; Sepsis - physiopathology; Severity of Illness Index; Studies; T cells; Tryptophan; Tryptophan - blood; Tryptophan 2,3-dioxygenase; Vasodilation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021185

Both endothelial and immune dysfunction contribute to the high mortality rate in human sepsis, but the underlying mechanisms are unclear. In response to infection, interferon-γ activates indoleamine 2,3-dioxygenase (IDO) which metabolizes the essential amino acid tryptophan to the toxic metabolite kynurenine. IDO can be expressed in endothelial cells, hepatocytes and mononuclear leukocytes, all of which contribute to sepsis pathophysiology. Increased IDO activity (measured by the kynurenine to tryptophan [KT] ratio in plasma) causes T-cell apoptosis, vasodilation and nitric oxide synthase inhibition. We hypothesized that IDO activity in sepsis would be related to plasma interferon-γ, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity, a measure of endothelial nitric oxide bioavailability. In an observational cohort study of 80 sepsis patients (50 severe and 30 non-severe) and 40 hospital controls, we determined the relationship between IDO activity (plasma KT ratio) and selected plasma cytokines, sepsis severity, nitric oxide-dependent microvascular reactivity and lymphocyte subsets in sepsis. Plasma amino acids were measured by high performance liquid chromatography and microvascular reactivity by peripheral arterial tonometry. The plasma KT ratio was increased in sepsis (median 141 [IQR 64-235]) compared to controls (36 [28-52]); p