Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis.
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.
Clinical Surgery, The University of Edinburgh, United Kingdom.
Christos
C
Skouras
Medical Research Council, Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, United Kingdom.
Xiaozhong
X
Zheng
University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom.
Margaret
M
Binnie
Mass Spectrometry Core, Edinburgh Clinical Research Facility, The University of Edinburgh, United Kingdom.
Natalie Z M
NZ
Homer
Medical Research Council, Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, United Kingdom.
Toby B J
TB
Murray
GlaxoSmithKline, Stevenage, United Kingdom.
Darren
D
Robertson
Wellcome Trust Clinical Research Facility, The University of Edinburgh, United Kingdom.
Lesley
L
Briody
Wellcome Trust Clinical Research Facility, The University of Edinburgh, United Kingdom.
Finny
F
Paterson
Wellcome Trust Clinical Research Facility, The University of Edinburgh, United Kingdom.
Heather
H
Spence
Wellcome Trust Clinical Research Facility, The University of Edinburgh, United Kingdom.
Lisa
L
Derr
Medical Research Council, Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, United Kingdom.
Alastair J
AJ
Hayes
National Technical University of Athens, Greece.
Andreas
A
Tsoumanis
Edinburgh and Lothians Laboratory Medicine, United Kingdom.
Dawn
D
Lyster
Clinical Surgery, The University of Edinburgh, United Kingdom.
Rowan W
RW
Parks
Clinical Surgery, The University of Edinburgh, United Kingdom.
O James
OJ
Garden
Medical Research Council, Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, United Kingdom.
John P
JP
Iredale
Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, United Kingdom.
Iain J
IJ
Uings
Discovery Partnerships with Academia, GlaxoSmithKline, Stevenage, United Kingdom.
John
J
Liddle
Bioanalysis, Immunogenicity and Biomarkers, GlaxoSmithKline, Ware, United Kingdom.
Wayne L
WL
Wright
Academic Discovery Performance Unit, Alternative Discovery &Development, GSK, Raleigh, North Carolina, United States of America.
George
G
Dukes
University/British Heart Foundation Centre for Cardiovascular Science, The University of Edinburgh, United Kingdom.
Scott P
SP
Webster
Clinical Surgery, The University of Edinburgh, United Kingdom.|Medical Research Council, Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, United Kingdom.
Damian J
DJ
Mole
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