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

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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.


The kynurenine pathway of tryptophan metabolism.The key step of kynurenine conversion to 3-hydroxykynurenine via the action of the gate-keeper enzyme kynurenine 3-monooxygenase (KMO), is highlighted.
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f1: The kynurenine pathway of tryptophan metabolism.The key step of kynurenine conversion to 3-hydroxykynurenine via the action of the gate-keeper enzyme kynurenine 3-monooxygenase (KMO), is highlighted.

Mentions: The exact pathological mechanisms that drive AP–MODS remain unclear, but the kynurenine pathway of tryptophan metabolism (Fig. 1) is emerging as a potentially important contributory mechanism78. In an inflammatory context, metabolism of tryptophan through the kynurenine pathway is dramatically increased through induction of indoleamine 2,3-dioxygenase (IDO) expression by pro-inflammatory cytokines, in particular, interferon gamma (IFN-γ)9. IDO upregulation increases substrate flux through downstream enzymes, in particular kynurenine 3-monooxygenase (KMO), thereby generating biologically–active metabolites that participate in multiple physiological and pathological processes101112131415. In rodent models of AP, 3-hydroxykynurenine, the product of the gate-keeper enzyme kynurenine 3-monooxygenase (KMO), appears to be critical to the pathogenesis of AP-MODS7. 3-hydroxykynurenine causes tissue injury via oxidative stress and pathological cross-linking of proteins16. Therapeutic blockade of KMO by genetic deletion in mice or pharmacological inhibition in rats reduces 3-hydroxykynurenine formation and protects against lung and kidney injury in experimental models of AP7. Other metabolites in the kynurenine pathway have been postulated to mediate immunological tolerance dependent on signalling via the aryl hydrocarbon receptor, whilst kynurenine specifically may contribute to T-helper Th17 and T-regulatory lymphocyte differentiation1718.


Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis
The kynurenine pathway of tryptophan metabolism.The key step of kynurenine conversion to 3-hydroxykynurenine via the action of the gate-keeper enzyme kynurenine 3-monooxygenase (KMO), is highlighted.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: The kynurenine pathway of tryptophan metabolism.The key step of kynurenine conversion to 3-hydroxykynurenine via the action of the gate-keeper enzyme kynurenine 3-monooxygenase (KMO), is highlighted.
Mentions: The exact pathological mechanisms that drive AP–MODS remain unclear, but the kynurenine pathway of tryptophan metabolism (Fig. 1) is emerging as a potentially important contributory mechanism78. In an inflammatory context, metabolism of tryptophan through the kynurenine pathway is dramatically increased through induction of indoleamine 2,3-dioxygenase (IDO) expression by pro-inflammatory cytokines, in particular, interferon gamma (IFN-γ)9. IDO upregulation increases substrate flux through downstream enzymes, in particular kynurenine 3-monooxygenase (KMO), thereby generating biologically–active metabolites that participate in multiple physiological and pathological processes101112131415. In rodent models of AP, 3-hydroxykynurenine, the product of the gate-keeper enzyme kynurenine 3-monooxygenase (KMO), appears to be critical to the pathogenesis of AP-MODS7. 3-hydroxykynurenine causes tissue injury via oxidative stress and pathological cross-linking of proteins16. Therapeutic blockade of KMO by genetic deletion in mice or pharmacological inhibition in rats reduces 3-hydroxykynurenine formation and protects against lung and kidney injury in experimental models of AP7. Other metabolites in the kynurenine pathway have been postulated to mediate immunological tolerance dependent on signalling via the aryl hydrocarbon receptor, whilst kynurenine specifically may contribute to T-helper Th17 and T-regulatory lymphocyte differentiation1718.

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.