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Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis

View Article: PubMed Central - PubMed

ABSTRACT

Inhibition of kynurenine 3-monooxygenase (KMO) protects against multiple organ dysfunction (MODS) in experimental acute pancreatitis (AP). We aimed to precisely define the kynurenine pathway activation in relation to AP and AP-MODS in humans, by carrying out a prospective observational study of all persons presenting with a potential diagnosis of AP for 90 days. We sampled peripheral venous blood at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. We measured tryptophan metabolite concentrations and analysed these in the context of clinical data and disease severity indices, cytokine profiles and C-reactive protein (CRP) concentrations. 79 individuals were recruited (median age: 59.6 years; 47 males, 59.5%). 57 met the revised Atlanta definition of AP: 25 had mild, 23 moderate, and 9 severe AP. Plasma 3-hydroxykynurenine concentrations correlated with contemporaneous APACHE II scores (R2 = 0.273; Spearman rho = 0.581; P < 0.001) and CRP (R2 = 0.132; Spearman rho = 0.455, P < 0.001). Temporal profiling showed early tryptophan depletion and contemporaneous 3-hydroxykynurenine elevation. Furthermore, plasma concentrations of 3-hydroxykynurenine paralleled systemic inflammation and AP severity. These findings support the rationale for investigating early intervention with a KMO inhibitor, with the aim of reducing the incidence and severity of AP-associated organ dysfunction.

No MeSH data available.


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Dot-plots of correlations between (a) Plasma concentrations of C-reactive protein and 3-hydroxykynurenine, for the tAP cohort grouped by AP severity (mild AP n = 25; moderate AP n = 23; severe AP n = 9). Data points represent means; error bars show standard deviation on both axes. The dashed red line represents mean 3-hydroxykynurenine plasma concentration in healthy volunteers (n = 8). (b) APACHE II score and contemporaneous log10 3-hydroxykynurenine plasma concentrations. Due to the non-normal distribution of plasma concentrations of of 3-hydroxykynurenine, a logarithmic transformation was used for the correlation to provide a better fit. For both correlations, results from samples obtained from T0 up to and including T48 were analysed. Results of respective Spearman correlations have been appended on each figure of the panel.
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f6: Dot-plots of correlations between (a) Plasma concentrations of C-reactive protein and 3-hydroxykynurenine, for the tAP cohort grouped by AP severity (mild AP n = 25; moderate AP n = 23; severe AP n = 9). Data points represent means; error bars show standard deviation on both axes. The dashed red line represents mean 3-hydroxykynurenine plasma concentration in healthy volunteers (n = 8). (b) APACHE II score and contemporaneous log10 3-hydroxykynurenine plasma concentrations. Due to the non-normal distribution of plasma concentrations of of 3-hydroxykynurenine, a logarithmic transformation was used for the correlation to provide a better fit. For both correlations, results from samples obtained from T0 up to and including T48 were analysed. Results of respective Spearman correlations have been appended on each figure of the panel.

Mentions: When considering all samples obtained from T0 up to and including T48, logarithmic 3-hydroxykynurenine levels correlated well with contemporaneous CRP (R2 = 0.132; rho = 0.455, P < 0.001) (Fig. 6a) and APACHE II score (R2 = 0.250; rho = 0.583; P < 0.001) (Fig. 6b). Furthermore, moderate correlation of logarithmic 3-hydroxykynurenine was discovered with contemporaneous levels of TFF3 (rho = 0.604, P < 0.001), albumin (rho = −0.568, P < 0.001), creatinine (rho = 0.531, P < 0.001), TNF-a (rho = 0.462, P < 0.001), and RAGE (rho = 0.455, P < 0.001), and weaker correlation with IL-10 (rho = 0.357, P < 0.001), IL-6 (rho = 0.352, P < 0.001), IL-17a (rho = 0.349, P < 0.001), CD163 (rho = 0.298, P < 0.001), IL-8 (rho = 0.293, P < 0.001), TNFS10 (rho = −0.259, P < 0.001), chemerin (rho = 0.247, P < 0.001), IL-1 (rho = 0.220, P < 0.001), insulin C-peptide (rho = 0.230, P < 0.001), cardiac troponin I (rho = 0.217, P < 0.001), CXCL12 (rho = 0.195, P = 0.001), and CD40 ligand (rho = 0.181, P = 0.003). Conversely, no correlation was found with insulin (rho = 0.057, P = 0.352), CA 15-3 (rho = −0.079, P = 0.199), B7-H1 (rho = −0.062, P = 0.312), and IFN-γ (rho = −0.019, P = 0.758). Differences between participant groups for all studied cytokines are summarized in Supplementary Table S3, and post-hoc pairwise comparisons of significantly different standardized AUC are depicted on Supplementary Table 4.


Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis
Dot-plots of correlations between (a) Plasma concentrations of C-reactive protein and 3-hydroxykynurenine, for the tAP cohort grouped by AP severity (mild AP n = 25; moderate AP n = 23; severe AP n = 9). Data points represent means; error bars show standard deviation on both axes. The dashed red line represents mean 3-hydroxykynurenine plasma concentration in healthy volunteers (n = 8). (b) APACHE II score and contemporaneous log10 3-hydroxykynurenine plasma concentrations. Due to the non-normal distribution of plasma concentrations of of 3-hydroxykynurenine, a logarithmic transformation was used for the correlation to provide a better fit. For both correlations, results from samples obtained from T0 up to and including T48 were analysed. Results of respective Spearman correlations have been appended on each figure of the panel.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037401&req=5

f6: Dot-plots of correlations between (a) Plasma concentrations of C-reactive protein and 3-hydroxykynurenine, for the tAP cohort grouped by AP severity (mild AP n = 25; moderate AP n = 23; severe AP n = 9). Data points represent means; error bars show standard deviation on both axes. The dashed red line represents mean 3-hydroxykynurenine plasma concentration in healthy volunteers (n = 8). (b) APACHE II score and contemporaneous log10 3-hydroxykynurenine plasma concentrations. Due to the non-normal distribution of plasma concentrations of of 3-hydroxykynurenine, a logarithmic transformation was used for the correlation to provide a better fit. For both correlations, results from samples obtained from T0 up to and including T48 were analysed. Results of respective Spearman correlations have been appended on each figure of the panel.
Mentions: When considering all samples obtained from T0 up to and including T48, logarithmic 3-hydroxykynurenine levels correlated well with contemporaneous CRP (R2 = 0.132; rho = 0.455, P < 0.001) (Fig. 6a) and APACHE II score (R2 = 0.250; rho = 0.583; P < 0.001) (Fig. 6b). Furthermore, moderate correlation of logarithmic 3-hydroxykynurenine was discovered with contemporaneous levels of TFF3 (rho = 0.604, P < 0.001), albumin (rho = −0.568, P < 0.001), creatinine (rho = 0.531, P < 0.001), TNF-a (rho = 0.462, P < 0.001), and RAGE (rho = 0.455, P < 0.001), and weaker correlation with IL-10 (rho = 0.357, P < 0.001), IL-6 (rho = 0.352, P < 0.001), IL-17a (rho = 0.349, P < 0.001), CD163 (rho = 0.298, P < 0.001), IL-8 (rho = 0.293, P < 0.001), TNFS10 (rho = −0.259, P < 0.001), chemerin (rho = 0.247, P < 0.001), IL-1 (rho = 0.220, P < 0.001), insulin C-peptide (rho = 0.230, P < 0.001), cardiac troponin I (rho = 0.217, P < 0.001), CXCL12 (rho = 0.195, P = 0.001), and CD40 ligand (rho = 0.181, P = 0.003). Conversely, no correlation was found with insulin (rho = 0.057, P = 0.352), CA 15-3 (rho = −0.079, P = 0.199), B7-H1 (rho = −0.062, P = 0.312), and IFN-γ (rho = −0.019, P = 0.758). Differences between participant groups for all studied cytokines are summarized in Supplementary Table S3, and post-hoc pairwise comparisons of significantly different standardized AUC are depicted on Supplementary Table 4.

View Article: PubMed Central - PubMed

ABSTRACT

Inhibition of kynurenine 3-monooxygenase (KMO) protects against multiple organ dysfunction (MODS) in experimental acute pancreatitis (AP). We aimed to precisely define the kynurenine pathway activation in relation to AP and AP-MODS in humans, by carrying out a prospective observational study of all persons presenting with a potential diagnosis of AP for 90 days. We sampled peripheral venous blood at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. We measured tryptophan metabolite concentrations and analysed these in the context of clinical data and disease severity indices, cytokine profiles and C-reactive protein (CRP) concentrations. 79 individuals were recruited (median age: 59.6 years; 47 males, 59.5%). 57 met the revised Atlanta definition of AP: 25 had mild, 23 moderate, and 9 severe AP. Plasma 3-hydroxykynurenine concentrations correlated with contemporaneous APACHE II scores (R2&thinsp;=&thinsp;0.273; Spearman rho&thinsp;=&thinsp;0.581; P&thinsp;&lt;&thinsp;0.001) and CRP (R2&thinsp;=&thinsp;0.132; Spearman rho&thinsp;=&thinsp;0.455, P&thinsp;&lt;&thinsp;0.001). Temporal profiling showed early tryptophan depletion and contemporaneous 3-hydroxykynurenine elevation. Furthermore, plasma concentrations of 3-hydroxykynurenine paralleled systemic inflammation and AP severity. These findings support the rationale for investigating early intervention with a KMO inhibitor, with the aim of reducing the incidence and severity of AP-associated organ dysfunction.

No MeSH data available.


Related in: MedlinePlus