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

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 k...

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Autores principales:	Christabelle J Darcy, Joshua S Davis, Tonia Woodberry, Yvette R McNeil, Dianne P Stephens, Tsin W Yeo, Nicholas M Anstey
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/db7f53dc71ef47e58a9ff0cbc7ce165f
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spelling	oai:doaj.org-article:db7f53dc71ef47e58a9ff0cbc7ce165f2021-11-18T06:51:33ZAn observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.1932-620310.1371/journal.pone.0021185https://doaj.org/article/db7f53dc71ef47e58a9ff0cbc7ce165f2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21731667/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Both 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<0.0001), and correlated with plasma interferon-γ 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.Christabelle J DarcyJoshua S DavisTonia WoodberryYvette R McNeilDianne P StephensTsin W YeoNicholas M AnsteyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 6, p e21185 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christabelle J Darcy Joshua S Davis Tonia Woodberry Yvette R McNeil Dianne P Stephens Tsin W Yeo Nicholas M Anstey An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.
description	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<0.0001), and correlated with plasma interferon-γ 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.
format	article
author	Christabelle J Darcy Joshua S Davis Tonia Woodberry Yvette R McNeil Dianne P Stephens Tsin W Yeo Nicholas M Anstey
author_facet	Christabelle J Darcy Joshua S Davis Tonia Woodberry Yvette R McNeil Dianne P Stephens Tsin W Yeo Nicholas M Anstey
author_sort	Christabelle J Darcy
title	An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.
title_short	An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.
title_full	An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.
title_fullStr	An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.
title_full_unstemmed	An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.
title_sort	observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/db7f53dc71ef47e58a9ff0cbc7ce165f
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An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function.

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