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

Darcy, Christabelle J., Davis, Joshua S., Woodberry, Tonia, McNeil, Yvette R., Stephens, Dianne P., Yeo, Tsin W. and Anstey, Nicholas M. (2011). An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function. PLoS ONE,6(6):e21185.

Document type: Journal Article
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Title An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function
Author Darcy, Christabelle J.
Davis, Joshua S.
Woodberry, Tonia
McNeil, Yvette R.
Stephens, Dianne P.
Yeo, Tsin W.
Anstey, Nicholas M.
Journal Name PLoS ONE
Publication Date 2011
Volume Number 6
Issue Number 6
ISSN 1932-6203   (check CDU catalogue open catalogue search in new window)
Start Page e21185
Total Pages 8
Place of Publication United States
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DEST)
Abstract 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-c 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-c, 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,0.0001), and correlated with plasma interferon-c and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased from 162 [IQR 100–286] on day 0 to 89 [65–139] by day 7; p = 0.0006) and this decrease in KT ratio correlated with a decrease in the Sequential Organ Failure Assessment score (p,0.0001). IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology.
DOI http://dx.doi.org/10.1371/journal.pone.0021185   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)


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