Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

Online
ISSN
1437-4331
See all formats and pricing
More options …
Volume 52, Issue 4

Issues

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

Christabelle J. Darcy
  • Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Tonia Woodberry / Joshua S. Davis
  • Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • Infectious Diseases Department, Royal Darwin Hospital, Darwin, NT, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kim A. Piera
  • Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Yvette R. McNeil
  • Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Youwei Chen
  • Division of Hematology-Oncology, Duke University and Veterans’ Affairs Medical Centers, Durham, NC, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Tsin W. Yeo
  • Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • Infectious Diseases Department, Royal Darwin Hospital, Darwin, NT, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ J. Brice Weinberg
  • Division of Hematology-Oncology, Duke University and Veterans’ Affairs Medical Centers, Durham, NC, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Nicholas M. Anstey
  • Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, NT, Australia
  • Infectious Diseases Department, Royal Darwin Hospital, Darwin, NT, Australia
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2013-10-29 | DOI: https://doi.org/10.1515/cclm-2013-0698

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.

Keywords: hypoargininemia; L-arginine; plasma arginase activity; sepsis

References

  • 1.

    Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303–10.PubMedCrossrefGoogle Scholar

  • 2.

    McGown CC, Brookes ZL. Beneficial effects of statins on the microcirculation during sepsis: the role of nitric oxide. Br J Anaesth 2007;98:163–75.Google Scholar

  • 3.

    Trzeciak S, Cinel I, Phillip Dellinger R, Shapiro NI, Arnold RC, Parrillo JE, et al. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med 2008;15:399–413.Web of SciencePubMedCrossrefGoogle Scholar

  • 4.

    Davis JS, Anstey NM. Is plasma arginine concentration decreased in patients with sepsis? A systematic review and meta-analysis. Crit Care Med 2011;39:380–5.CrossrefWeb of ScienceGoogle Scholar

  • 5.

    Moncada S, Higgs EA. Nitric oxide and the vascular endothelium. Handb Exper Pharmacol 2006(176 Pt 1):213–54.Google Scholar

  • 6.

    Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 2005;5:641–54.CrossrefPubMedGoogle Scholar

  • 7.

    Darcy CJ, Davis JS, Woodberry T, McNeil YR, Stephens DP, Yeo TW, et al. An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function. PloS One 2011;6:e21185.Web of ScienceCrossrefGoogle Scholar

  • 8.

    Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, et al. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med 2007;204:2693–704.Google Scholar

  • 9.

    Luiking YC, Poeze M, Ramsay G, Deutz NE. Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr 2009;89:142–52.PubMedWeb of ScienceGoogle Scholar

  • 10.

    Arraes SM, Freitas MS, da Silva SV, de Paula Neto HA, Alves-Filho JC, Auxiliadora Martins M, et al. Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation. Blood 2006;108:2906–13.CrossrefGoogle Scholar

  • 11.

    Munder M, Mollinedo F, Calafat J, Canchado J, Gil-Lamaignere C, Fuentes JM, et al. Arginase I is constitutively expressed in human granulocytes and participates in fungicidal activity. Blood 2005;105:2549–56.Google Scholar

  • 12.

    Abebe T, Takele Y, Weldegebreal T, Cloke T, Closs E, Corset C, et al. Arginase activity – a marker of disease status in patients with visceral leishmaniasis in ethiopia. PLoS Negl Trop Dis 2013;7:e2134.CrossrefWeb of ScienceGoogle Scholar

  • 13.

    Jacobsen LC, Theilgaard-Monch K, Christensen EI, Borregaard N. Arginase 1 is expressed in myelocytes/metamyelocytes and localized in gelatinase granules of human neutrophils. Blood 2007;109:3084–7.Web of ScienceGoogle Scholar

  • 14.

    Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, et al. Arginase I-producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res 2009;69:1553–60.Web of ScienceGoogle Scholar

  • 15.

    Stone E, Chantranupong L, Gonzalez C, O′Neal J, Rani M, VanDenBerg C, et al. Strategies for optimizing the serum persistence of engineered human arginase I for cancer therapy. J Control Release 2012;158:171–9.Web of ScienceGoogle Scholar

  • 16.

    Reyero C, Dorner F. Purification of arginases from human-leukemic lymphocytes and granulocytes: study of their physicochemical and kinetic properties. Eur J Biochem 1975;56:137–47.Google Scholar

  • 17.

    Folley SJ, Greenbaum AL. Determination of the arginase activities of homogenates of liver and mammary gland: effects of pH and substrate concentration and especially of activation by divalent metal ions. Biochem J 1948;43:537–49.PubMedGoogle Scholar

  • 18.

    Rotondo R, Bertolotto M, Barisione G, Astigiano S, Mandruzzato S, Ottonello L, et al. Exocytosis of azurophil and arginase 1-containing granules by activated polymorphonuclear neutrophils is required to inhibit T lymphocyte proliferation. J Leukoc Biol 2011;89:721–7.PubMedWeb of ScienceGoogle Scholar

  • 19.

    Munder M, Schneider H, Luckner C, Giese T, Langhans CD, Fuentes JM, et al. Suppression of T-cell functions by human granulocyte arginase. Blood 2006;108:1627–34.Google Scholar

  • 20.

    Ihi T, Nakazato M, Mukae H, Matsukura S. Elevated concentrations of human neutrophil peptides in plasma, blood, and body fluids from patients with infections. Clin Infect Dis 1997;25:1134–40.CrossrefPubMedGoogle Scholar

  • 21.

    Panyutich AV, Panyutich EA, Krapivin VA, Baturevich EA, Ganz T. Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis. J Lab Clin Med 1993;122:202–7.Google Scholar

  • 22.

    Cheng PN, Leung YC, Lo WH, Tsui SM, Lam KC. Remission of hepatocellular carcinoma with arginine depletion induced by systemic release of endogenous hepatic arginase due to transhepatic arterial embolisation, augmented by high-dose insulin: arginase as a potential drug candidate for hepatocellular carcinoma. Cancer Lett 2005;224:67–80.Google Scholar

  • 23.

    Davis JS, Yeo TW, Thomas JH, McMillan M, Darcy CJ, McNeil YR, et al. Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study. Crit Care 2009;13:R155.CrossrefGoogle Scholar

  • 24.

    Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992;101:1644–55.Google Scholar

  • 25.

    Davis JS, Darcy CJ, Piera K, McNeil YR, Woodberry T, Anstey NM. Ex-vivo changes in amino acid concentrations from blood stored at room temperature or on ice: implications for arginine and taurine measurements. BMC Clin Pathol 2009; 9:10.CrossrefGoogle Scholar

  • 26.

    Fairbanks VF, Ziesmer SC, O′Brien PC. Methods for measuring plasma hemoglobin in micromolar concentration compared. Clin Chem 1992;38:132–40.PubMedGoogle Scholar

  • 27.

    Wang H, McNeil YR, Yeo TW, Anstey NM. Simultaneous determination of multiple amino acids in plasma in critical illness by high performance liquid chromatography with ultraviolet and fluorescence detection. J Chromatogr B 2013 (in press).Google Scholar

  • 28.

    Jones CE, Darcy CJ, Woodberry T, Anstey NM, McNeil YR. HPLC analysis of asymmetric dimethylarginine, symmetric dimethylarginine, homoarginine and arginine in small plasma volumes using a Gemini-NX column at high pH. J Chromatogr B Analyt Technol Biomed Life Sci 2010;878:8–12.Google Scholar

  • 29.

    Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. J Am Med Assoc 2005;294:81–90.Google Scholar

  • 30.

    Grisham MB, Everse J, Janssen HF. Endotoxemia and neutrophil activation in vivo. Am J Physiol 1988;254(5 Pt 2):H1017–22.Google Scholar

  • 31.

    Wong HR, Doughty LA, Wedel N, White M, Nelson BJ, Havrilla N, et al. Plasma bactericidal/permeability-increasing protein concentrations in critically ill children with the sepsis syndrome. Pediatr Infect Dis J 1995;14:1087–91.PubMedCrossrefGoogle Scholar

  • 32.

    Xu SY, Pauksen K, Venge P. Serum measurements of human neutrophil lipocalin (HNL) discriminate between acute bacterial and viral infections. Scand J Clin Lab Invest 1995;55:125–31.CrossrefPubMedGoogle Scholar

  • 33.

    Nuijens JH, Abbink JJ, Wachtfogel YT, Colman RW, Eerenberg AJ, Dors D, et al. Plasma elastase alpha 1-antitrypsin and lactoferrin in sepsis: evidence for neutrophils as mediators in fatal sepsis. J Lab Clin Med 1992;119:159–68.Google Scholar

  • 34.

    Ertel W, Jarrar D, Jochum M, Thiele V, Kenney J, Faist E, et al. Enhanced release of elastase is not concomitant with increased secretion of granulocyte-activating cytokines in whole blood from patients with sepsis. Arch Surg 1994;129:90–7; discussion 7–8.Google Scholar

  • 35.

    Rodriguez-Garcia M, Oliva H, Climent N, Garcia F, Gatell JM, Gallart T. Human immature monocyte-derived dendritic cells produce and secrete alpha-defensins 1-3. J Leukoc Biol 2007;82:1143–6.Web of ScienceCrossrefGoogle Scholar

  • 36.

    Morris SM Jr. Recent advances in arginine metabolism: roles and regulation of the arginases. Br J Pharmacol 2009;157:922–30.Web of ScienceGoogle Scholar

  • 37.

    Ochoa JB, Bernard AC, O′Brien WE, Griffen MM, Maley ME, Rockich AK, et al. Arginase I expression and activity in human mononuclear cells after injury. Ann Surg 2001;233:393–9.Google Scholar

  • 38.

    Zea AH, Culotta KS, Ali J, Mason C, Park HJ, Zabaleta J, et al. Decreased expression of CD3zeta and nuclear transcription factor kappa B in patients with pulmonary tuberculosis: potential mechanisms and reversibility with treatment. J Infect Dis 2006;194:1385–93.Google Scholar

  • 39.

    Corraliza I, Moncada S. Increased expression of arginase II in patients with different forms of arthritis. Implications of the regulation of nitric oxide. J Rheumatol 2002;29:2261–5.PubMedGoogle Scholar

  • 40.

    Zimmermann N, King NE, Laporte J, Yang M, Mishra A, Pope SM, et al. Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis. J Clin Invest 2003;111:1863–74.Google Scholar

  • 41.

    Bruch-Gerharz D, Schnorr O, Suschek C, Beck KF, Pfeilschifter J, Ruzicka T, et al. Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation. Am J Pathol 2003;162:203–11.Google Scholar

  • 42.

    Rouzaut A, Subira ML, de Miguel C, Domingo-de-Miguel E, Gonzalez A, Santiago E, et al. Co-expression of inducible nitric oxide synthase and arginases in different human monocyte subsets. Apoptosis regulated by endogenous NO. Biochim Biophys Acta 1999;1451:319–33.Google Scholar

  • 43.

    Brown KA, Brain SD, Pearson JD, Edgeworth JD, Lewis SM, Treacher DF. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006;368:157–69.Google Scholar

  • 44.

    Nast-Kolb D, Waydhas C, Gippner-Steppert C, Schneider I, Trupka A, Ruchholtz S, et al. Indicators of the posttraumatic inflammatory response correlate with organ failure in patients with multiple injuries. J Trauma 1997;42:446–54; discussion 54–5.CrossrefGoogle Scholar

About the article

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.


Received: 2013-08-27

Accepted: 2013-10-08

Published Online: 2013-10-29

Published in Print: 2014-04-01


Citation Information: Clinical Chemistry and Laboratory Medicine, Volume 52, Issue 4, Pages 573–581, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2013-0698.

Export Citation

©2014 by Walter de Gruyter Berlin/Boston.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Johnny Moretto, Corine Girard, and Céline Demougeot
Experimental Gerontology, 2019, Volume 116, Page 54
[2]
Anastasia Kyselova, Hanna Hinrichsmeyer, Sven Zukunft, Alexander W. Mann, Imke Dornauf, Ingrid Fleming, and Voahanginirina Randriamboavonjy
Metabolism, 2018
[3]
Jeanette Wagener, Donna M. MacCallum, Gordon D. Brown, Neil A. R. Gow, and Tamara L. Doering
mBio, 2017, Volume 8, Number 1
[4]
Sophie Yacoub, Phung Khanh Lam, Trieu Trung Huynh, Hong Hanh Nguyen Ho, Hoai Tam Dong Thi, Nguyen Thu Van, Le Thi Lien, Quyen Nguyen Than Ha, Duyen Huynh Thi Le, Juthathip Mongkolspaya, Abigail Culshaw, Tsin Wen Yeo, Heiman Wertheim, Cameron Simmons, Gavin Screaton, and Bridget Wills
Clinical Infectious Diseases, 2017, Volume 65, Number 9, Page 1453
[5]
Benard W Kulohoma, Fiona Marriage, Olga Vasieva, Limangeni Mankhambo, Kha Nguyen, Malcolm E Molyneux, Elizabeth M Molyneux, Philip J R Day, and Enitan D Carrol
BMJ Paediatrics Open, 2017, Volume 1, Number 1, Page e000092
[6]
Claudia R. Morris, Jill Hamilton-Reeves, Robert G. Martindale, Menaka Sarav, and Juan B. Ochoa Gautier
Nutrition in Clinical Practice, 2017, Volume 32, Number 1_suppl, Page 30S
[7]
Karolina Wijnands, Tessy Castermans, Merel Hommen, Dennis Meesters, and Martijn Poeze
Nutrients, 2015, Volume 7, Number 3, Page 1426
[8]
Paweł Karpiński, Dorota Frydecka, Maria M. Sąsiadek, and Błażej Misiak
Brain, Behavior, and Immunity, 2016, Volume 54, Page 194

Comments (0)

Please log in or register to comment.
Log in