An observational cohort study of the kynurenine to tryptophan ratio in sepsis

association with impaired immune and microvascular function

Christabelle Darcy, Joshua Davis, Tonia Woodberry, Yvette McNeil, Dianne P Stephens, Tsin Yeo, Nicholas Anstey

    Research output: Contribution to journalArticleResearchpeer-review

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    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-? 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-?, 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-? 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.
    Original languageEnglish
    Article numbere21185
    Pages (from-to)1-8
    Number of pages8
    JournalPLoS One
    Volume6
    Issue number6
    DOIs
    Publication statusPublished - 2011

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    kynurenine
    Kynurenine
    sepsis (infection)
    Indoleamine-Pyrrole 2,3,-Dioxygenase
    cohort studies
    Tryptophan
    tryptophan
    Observational Studies
    Sepsis
    Cohort Studies
    Association reactions
    Plasmas
    T-cells
    interferons
    Interferons
    Lymphocytes
    T-lymphocytes
    Interleukin-10
    interleukin-10
    pathophysiology

    Cite this

    Darcy, Christabelle ; Davis, Joshua ; Woodberry, Tonia ; McNeil, Yvette ; Stephens, Dianne P ; Yeo, Tsin ; Anstey, Nicholas. / An observational cohort study of the kynurenine to tryptophan ratio in sepsis : association with impaired immune and microvascular function. In: PLoS One. 2011 ; Vol. 6, No. 6. pp. 1-8.
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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; Davis, Joshua; Woodberry, Tonia; McNeil, Yvette; Stephens, Dianne P; Yeo, Tsin; Anstey, Nicholas.

    In: PLoS One, Vol. 6, No. 6, e21185, 2011, p. 1-8.

    Research output: Contribution to journalArticleResearchpeer-review

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    N2 - 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-? 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-?, 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-? 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.

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