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Tryptophan metabolism to kynurenine is a potential novel contributor to hypotension in human sepsis*

Changsirivathanathamrong, Dechaboon MBBS, FRACP; Wang, Yutang PhD; Rajbhandari, Dorrilyn RN, Post Grad Dip (Clinical Nursing); Maghzal, Ghassan J. PhD; Mak, Wendy M. PhD; Woolfe, Clive FJFICM F ANZCA; Duflou, Johan MMed, FRCPA; Gebski, Val BA, MStat; dos Remedios, Cris G. DSc; Celermajer, David S. MBBS, FRACP, PhD; Stocker, Roland PhD

doi: 10.1097/CCM.0b013e31822827f2
Clinical Investigations

Objectives: To determine whether tryptophan metabolism to kynurenine contributes to the direct regulation of vascular tone in human septic shock.

Background: Indoleamine 2,3-dioxygenase 1 is an inducible enzyme that converts tryptophan to kynurenine and shares functional similarities with inducible nitric oxide synthase. Recently, kynurenine has been identified as an endothelium-derived relaxing factor produced during inflammation, raising the possibility that this novel pathway may contribute to hypotension in human sepsis.

Design: Prospective, matched, single-center, cohort study.

Settings: Intensive care unit of a tertiary teaching hospital matched to control subjects from the general medical ward and healthy volunteers.

Subjects: Patients (n = 16) with septic shock had indoleamine 2,3-dioxygenase activity assessed as the kynurenine-to-tryptophan ratio, and the severity of hypotension was determined by their inotrope requirements. Healthy and blood pressure-matched nonseptic control subjects were also studied.

Interventions: None.

Measurements and Main Results: Tissues from septic and control patients were stained for the presence of indoleamine 2,3-dioxygenase 1. Indoleamine 2,3-dioxygenase activity increased up to ninefold in patients with septic shock and was significantly higher than in the two control groups (p < .01). Indoleamine 2,3-dioxygenase activity was strongly correlated with inotrope requirements (p < .001). Indoleamine 2,3-dioxygenase protein was expressed in inflamed cardiac tissue as well as in endothelial cells of resistance vessels in hearts and kidneys from subjects who died from sepsis.

Conclusions: Indoleamine 2,3-dioxygenase 1 is expressed in resistance vessels in human sepsis and Indoleamine 2,3-dioxygenase activity correlates with hypotension in human septic shock. Indoleamine 2,3-dioxygenase 1 is thus a potential novel contributor to hypotension in sepsis.

From the Centre for Vascular Research (DC, YW, GJM, WMM, RS), School of Medical Sciences (Pathology) and Bosch Institute, Sydney, Australia; Royal Prince Alfred Hospital (DC, DR, CW, DSC), Sydney, Australia; the Department of Forensic Medicine Sydney (JD), Sydney, Australia; NHMRC Clinical Trials Centre (VG), Sydney, Australia; and the School of Medical Sciences (Anatomy) and Bosch Institute (CGdR), The University of Sydney, Sydney NSW, Australia.

This work was supported by an Australian Postgraduate Scholarship from the Commonwealth Government of Australia (to Dr. Changsirivathanathamrong), Project Grant 570861 from the National Health & Medical Research Council (NHMRC) of Australia (to Dr. Stocker), and NHMRC Program Grants 455395 and 482800 to Drs. Stocker and Celermajer, respectively. Dr. Stocker is supported by a NHMRC Senior Principal Research Fellowship, a University of Sydney Professorial Fellowship, and the University of Sydney Medical Foundation.

Work presented in this article was performed at the Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute and Royal Prince Alfred Hospital, The University of Sydney, Sydney NSW, Australia.

Dr. Stocker received a grant from the National Health Medical Research Council. The remaining authors have not disclosed any potential conflicts of interest.

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© 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins