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

Christos Skouras, Xiaozhong Zheng, Margaret Binnie, Natalie Z. M. Homer, Toby B J Murray, Darren Robertson, Lesley Briody, Finny Paterson, Heather Spence, Lisa Derr, Alastair J. Hayes, Andreas Tsoumanis, Dawn Lyster, Rowan W. Parks, O. James Garden, John P. Iredale, Iain J Uings, John Liddle, Wayne L Wright, George DukesScott P. Webster, Damian J. Mole

Research output: Contribution to journalArticlepeer-review

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 (R(2) = 0.273; Spearman rho = 0.581; P < 0.001) and CRP (R(2) = 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.

Original languageEnglish
Pages (from-to)33951
JournalScientific Reports
Volume6
Early online date27 Sep 2016
DOIs
Publication statusPublished - 2016

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