Effects of induced arginase enzyme on arginine availability for nitric oxide production in children with severe malaria
Loading...
Date
2013
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Hubert Kairuki Memorial University
Abstract
INTRODUCTION:
Malaria is still one of the major leading causesof morbidity and mortality in developing countries regardlessof the use of effective antimalarial drugs. Immunological response as a result of malaria acquisition contributes much to pathogenesis of malaria. Recent studies have indicated that malaria infection is associated with low plasma arginine levels with subsequent low NO productionand endothelial dysfunction. NO is important for normal endothelial function which is impaired during malaria infection. The causes ofhypoargininemiawith low NO production in malariaarenot well understood. Arginase,anenzyme responsiblefor metabolism of arginine to ornithine,competes with NOS for its substratearginine. Ornithine is a precursor for polyamine biosynthesis and other anabolicpathways. The contributionofarginase tothedevelopment of low plasma arginine levelshasnot been studied in children.
OBJECTIVES:
The aim of this study was to assess the role of plasmaArginasein the observedhypoargininemiain children with malaria.
METHODS:
Across-sectionprospective,observationalstudy was done in Dar es Salaam, Tanzania. Children aged 6 months to 9 years were recruited from Mwananyamala, Amana,and Mikocheni hospitals afterobtaining informedconsent. Participants were grouped into severe malaria(SM), uncomplicated malaria (UM),and healthy controls (HC) using WHO criteria. Blood samples were taken from participants and analyzed for plasmaarginine,plasmaarginaseactivity,andcell-freehemoglobin. PBMCswereseparated from anticoagulated bloodfor determination of mRNA for arginase1,arginase2,and NOS2.
RESULTS:
Eighty (80) SM, 80UM,and48HCwere recruited. Plasma arginine levels were significantly lower in malaria groups compared to healthy controls (p<0.0001).The mean values were 58.8±3.9µmol/L in SM, 54.8±3.3µmol/L in UM,and94.58±4.2 µmol/L inHC.Plasma arginase activity was higher in children with malaria, but it was not statistically significantly higher (p=0.75).Themean values were 0.273±0.034µmol/ml/hour inSM, 0.252±0.030µmol/ml/hour in UM,and 0.200±0.0566µmol/ml/hour in HC.There was no correlation between plasma arginase activity and plasma arginine levels in SM group (Pearson r=-0.001).Cell free Hb levels werehigher in the SM and UM groups (p=0.02), but it did not correlate with plasma arginase activity(r=-0.09). Therewas amarked increaseinarginase 1mRNAin PBMCs7 fromSM and UM compared to HC group. The median values were9.31and4.51fold increaseinSMandUMgroups,respectively (p=0.008 and 0.02,respectively).mRNA valuesfor arginase2 wereslightly higher in the HCgroup, but this was notsignificantly higherthan that of the other groups(p=0.89).NOS2 mRNA was lower in PBMC of malaria patients(SMand UM)compared toHC(p=0.0001foreachcomparison).
DISCUSSION, CONCLUSION,AND RECOMMENDATIONS:
Plasma arginine levels were lowin children with malariacomparedtopreviouslyreportedfindings. Hypoargininemiaand plasma arginase activity do notsignificantlycorrelate with one another. ElevatedarginaseImRNA levelsin PBMCpatients withmalaria,suggests that arginase 1 could alsobe induced in othermononuclear phagocytes, including fixed macrophages. These arginase1-bearing cells may in part beresponsible for hypoargininemia. Induction of mononuclear phagocyte arginase1anddiminished NOS2mRNA and NO production bymononuclear phagocytes conforms to the phenotype of “alternative macrophage activation.” Hypoargininemia and alternative macrophage activation correlate with clinical malaria and may be markers ofmalaria diseaseseverity.Assessment of arginase activity inPBMCs (andpurifiedmononuclear phagocytes)during malaria infection is warranted to fully establishtheroleof alternativelyactived monocytes-macrophagesinthehypoarginaemia observed during themalaria infection.
Description
A dissertation submitted in partial fulfillment of the requirement for the degree of Master of Medicine (Pediatrics and child health) of the Hubert Kairuki Memorial University
Keywords
Arginase enzyme, Nitric oxide production, Severe malaria
Citation
Kalabamu, F.S., 2013. Effects of induced arginase enzyme on arginine availability for Nitric oxide production in children with severe Malaria (Doctoral dissertation, HKMU).