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Licensed Unlicensed Requires Authentication Published by De Gruyter October 29, 2013

Increased plasma arginase activity in human sepsis: association with increased circulating neutrophils

  • Christabelle J. Darcy , Tonia Woodberry EMAIL logo , Joshua S. Davis , Kim A. Piera , Yvette R. McNeil , Youwei Chen , Tsin W. Yeo , J. Brice Weinberg and Nicholas M. Anstey

Abstract

Background: The pathophysiology of sepsis is incompletely understood. Impaired bioavailability of L-arginine, the substrate for NO synthesis, is linked to sepsis severity, and plasma arginase has been linked to hypoargininemia in other disease states. Circulating neutrophils are increased in sepsis and constitutively express arginase. We investigated whether plasma arginase activity is increased in human sepsis and whether this is associated with neutrophil numbers and activation.

Methods: We used HPLC and a radiometric assay to evaluate plasma amino acid concentrations and plasma arginase activity. The relationships between plasma arginase activity, neutrophil count, neutrophil activity and plasma L-arginine and arginine metabolites were evaluated in 44 sepsis patients and 25 controls.

Results: Plasma arginase activity was increased in sepsis patients, correlated with neutrophil count (r=0.44; p=0.003), but was independent of sepsis severity (SOFA or APACHE II score). Plasma HNP1-3 correlated with neutrophil count (r=0.31; p=0.04), was elevated in shock (median 180 ng/mL vs. 83 ng/mL sepsis without shock, p=0.0006) and correlated with SOFA score. Sepsis patients with high neutrophil counts had significantly higher plasma HNP1-3 and arginase activity and lower plasma L-arginine concentrations than those with lower neutrophil counts and controls.

Conclusions: Plasma arginase activity, potentially derived in part from neutrophil activation, is elevated in sepsis, and may contribute to impaired bioavailability of L-arginine in sepsis.


Corresponding author: Tonia Woodberry, Menzies School of Health Research, PO Box 41096, Casuarina, NT 0811, Australia, Phone: +61 8 8922 8196, Fax: +61 8 8927 5187, E-mail:
aChristabelle J. Darcy and Tonia Woodberry contributed equally.

Acknowledgments

We thank Dianne Stephens, Jane Thomas and Mark McMillan for help with patient recruitment and the medical and nursing staff of the Royal Darwin Hospital Intensive Care Unit, Division of Medicine and Hospital in the Home for assistance with sample collection.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding played no role in thestudy design; in the collection, analysis, and interpretationof data; in the writing of the report; or in the decision tosubmit the report for publication.

Research funding: This study was funded by the National Health and Medical Research Council of Australia (Program Grants 290208, 496600; Practitioner Fellowship to NMA, Scholarship to JSD); and the U.S. Veterans Affairs Research Service and NIH grant R01- AI041764 (JBW).

Employment or leadership: None declared.

Honorarium: None declared.

Author’s contributions: Study design was performed by CJD, JSD, TW, YRM, TWY and NMA. Patient recruitment was carried out by JSD. Laboratory sample processing was performed by CJD, KAP and TW. HPLC assays were undertaken by YRM and CJD. Arginase activity assays were performed by YC with assistance from BJW. The data were analyzed by CJD with help from JSD and NMA. The manuscript was drafted by CJD, JSD, TW and NMA. All authors had access to all data and contributed to the final draft of the paper. All authors read and approved the final manuscript.

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Received: 2013-8-27
Accepted: 2013-10-8
Published Online: 2013-10-29
Published in Print: 2014-04-01

©2014 by Walter de Gruyter Berlin/Boston

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