The subtle balance between proinflammatory and antiinflammatory cytokines plays an important role in determining the severity of the inflammatory reaction and in the anomalous iron handling associated with infection. Conversely, iron deficiency per se appears to limit the severity of the inflammatory response. All of these considerations are at present highly speculative and in need of further experimental and epidemiologic support. If confirmed, the beneficial biological effects of iron depletion may have a defensive role in inflammation and may be perturbed by the nonselective administration of iron to iron-replete patients who would not benefit from such treatment in the first place. In view of the importance of non-transferrin-bound plasma iron (NTBI) in iron toxicity and its rapid cellular uptake, it may play an important role in the harmful effects of iron in infection, and this is illustrated by the infectious complications of parenteral iron therapy in tropical countries.
HalliwellBGutteridgeJM. Biologically relevant metal ion-dependent hydroxyl radical generation. An update. FEBS Lett1992;307:108–12.
2.
CadenasE. Biochemistry of oxygen toxicity. Annu Rev Biochem1989;58:79–110.
3.
KadiiskaMBBurkittMJXiangQHMasonRP. Iron supplementation generates hydroxyl radical in vivo. An ESR spin-trapping investigation. J Clin Invest1995;96:1653–7.
4.
RichterCGogvadzeVLaffranchiRSchlapbachRSchweizerMSuterMWalterPYaffeeM. Oxidants in mitochondria: From physiology to diseases. Biochim Biophys Acta1995;1271:67–74.
5.
FryMGreenDE. Cardiolipin requirement by cytochrome oxidase and the catalytic role of phospholipid. Biochem Biophys Res Commun1980;93:1238–46.
6.
GoormaghtighEBrasseurRRuysschaertJM. Adriamycin inactivates cytochrome C oxidase by exclusion of the enzyme from its cardiolipin essential environment. Biochem Biophys Res Commun1982;104:314–20.
7.
HouglumKFilipMWitztumJLChojkierM. Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload. J Clin Invest1990;86:1991–8.
8.
StadtmanER. Metal ion-catalyzed oxidation of proteins: Biochemical mechanism and biological consequences. Free Radic Biol Med1990;9:315–25.
9.
HealesSJDaviesSEBatesTEClarkJB. Depletion of brain glutathione is accompanied by impaired mitochondrial function and decreased N-acetyl aspartate concentration. Neurochem Res1995;20:31–8.
10.
ZagerA. Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria. Kidney Int1996;49:741–51.
11.
PitkainenSRobinsonBH. Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase. J Clin Invest1996;98:345–51.
12.
RothmanRJSerroniAFarberJL. Cellular pool of transient ferric iron, chelatable by deferoxamine and distinct from ferritin, that is involved in oxidative cell injury. Mol Pharmacol1992;42:703–10.
13.
KlausnerRDRouaultTAHarfordJB. Regulating the fate of mRNA: The control of cellular iron metabolism. Cell1993;72:19–28.
14.
BreuerWEpsztejnSCabantchikZI. Dynamics of the cytosolic chelatable iron pool of K562 cells. FEBS Lett1996;382:304–8.
15.
HershkoCGrahamGBatesGWRachmilewitzEA. Non-specific serum iron in thalassaemia: An abnormal serum iron fraction of potential toxicity. Br J Haematol1978;40:255–63.
16.
SinghSHiderRCPorterJB. A direct method for quantification of non-transferrin bound iron (NTBI). Anal Biochem1990;186:320–3.
17.
AnuwatanakulchaiMPootrakulPThuvasethakulPWasiP. Non-transferrin plasma iron in β-thalassaemia/HbE and haemoglobin H diseases. Scand J Haematol1984;32:153–8.
18.
WagstaffMPetersSWJonesBMJacobsA. Free iron and iron toxicity in iron overload. Br J Haematol1985;61:566–7.
19.
GutteridgeJMRowleyDAGriffithsEHalliwellB. Low-molecular-weight iron complexes and oxygen radical reactions in idiopathic haemochromatosis. Clin Sci (Lond)1985;68:463–7.
20.
al-RefaieFNWickensDGWonkeBKontoghiorghesGJHoffbrandAV. Serum non-transferrin-bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1. Br J Haematol1992;82:431–6.
21.
PorterJBAbeysingheRDMarshallLHiderRCSinghS. Kinetics of removal and reappearance of non-transferrin-bound plasma iron with deferoxamine therapy. Blood1996;88:705–13.
22.
LinkGPinsonAHershkoC. Heart cells in culture: A model of myocardial iron overload and chelation. J Lab Clin Med1985;106:147–53.
23.
RandellEWParkesJGOlivieriNFTempletonDM. Uptake of non-transferrin-bound iron by both reductive and nonreductive processes is modulated by intracellular iron. J Biol Chem1994;269:16046–53.
24.
Le LanCLoréalOCohenTRopertMGlicksteinHLainéFPouchardMDeugnierYLe TreutABreuerWCabantchikZIBrissotP. Redox active plasma iron in C282Y/C282Y hemochromatosis. Blood2005;105:4527–31.
25.
JensenPDJensenFTChristensenTEiskjaerHBaandrupUNielsenJL. Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with desferrioxamine: Indication of close relation between myocardial iron content and chelatable iron pool. Blood2003;101:4632–9.
26.
JensenPDJensenFTChristensenTNielsenJLEllegaardJ. Relationship between hepatocellular injury and transfusional iron overload prior to and during iron chelation with desferrioxamine: A study in adult patients with acquired anemias. Blood2003;101:91–6.
27.
MakITWeglickiWB. Characterization of iron-mediated peroxidative injury in isolated hepatic lysosomes. J Clin Invest1985;75:58–63.
28.
SeymourCAPetersTJ. Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes. Br J Haematol1978;40:239–53.
29.
LinkGPinsonAHershkoC. Iron loading of cultured cardiac myocytes modifies sarcolemmal structure and increases lysosomal fragility. J Lab Clin Med1993;121:127–34.
30.
BaconBRO'NeillRBrittonRS. Hepatic mitochondrial energy production in rats with chronic iron overload. Gastroenterology1993;105:1134–40.
31.
CeccarelliDGallesiDGiovanniniFFerraliMMasiniA. Relationship between free iron level and rat liver mitochondrial dysfunction in experimental dietary iron overload. Biochem Biophys Res Commun1995;209:53–9.
32.
LinkGSaadaAPinsonAKonijnAMHershkoC. Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells. J Lab Clin Med1998;131:466–74.
33.
RobinsonBHGlerumDMChowWPetrova-BenedictRLightowlersRCapaldiR. The use of skin fibroblast cultures in the detection of respiratory chain defects in patients with lactic acidemia. Pediatr Res1990;28:549–55.
34.
HatefiY. Preparation and properties of NADH: Ubiquinone oxidoreductase (complex I) ECI6.5.3. Methods Enzymol1978;53:11–4.
35.
ZhangYMarcillatOGiuliviCErnsterLDaviesKJ. The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J Biol Chem1990;265:16330–6.
36.
McKnightRCHunterFEJr. Mitochondrial membrane ghosts produced by lipid peroxidation induced by ferrous ion. II. Composition and enzymatic activity. J Biol Chem1966;241:2757–65.
37.
BellomoGMartinoARichelmiPMooreGAJewellSAOrreniusS. Pyridine-nucleotide oxidation, Ca2+ cycling and membrane damage during tert-butyl hydroperoxide metabolism by rat-liver mitochondria. Eur J Biochem1984;140:1–6.
38.
FreiBWinterhalterKHRichterC. Quantitative and mechanistic aspects of the hydroperoxide-induced release of Ca2+ from rat liver mitochondria. Eur J Biochem1985;149:633–9.
39.
LotscherHRWinterhalterKHCarafoliERichterC. Hydroperoxides can modulate the redox state of pyridine nucleotides and the calcium balance in rat liver mitochondria. Proc Natl Acad Sci USA1979;76:4340–4.
40.
LotscherHRWinterhalterKHCarafoliERichterC. Hydroperoxide-induced loss of pyridine nucleotides and release of calcium from rat liver mitochondria. J Biol Chem1980;255:9325–30.
41.
LehningerALVercesiABababunmiEA. Regulation of Ca2+ release from mitochondria by the oxidation-reduction state of pyridine nucleotides. Proc Natl Acad Sci USA1978;75:1690–4.
42.
Al-NasserICromptonM. The reversible Ca2+-induced permeabilization of rat liver mitochondria. Biochem J1986;239:19–29.
43.
CromptonMCostiA. Kinetic evidence for a heart mitochondrial pore activated by Ca2+, inorganic phosphate and oxidative stress. A potential mechanism for mitochondrial dysfunction during cellular Ca2+ overload. Eur J Biochem1988;178:489–501.
44.
BellomoGJewellSAOrreniusS. The metabolism of menadione impairs the ability of rat liver mitochondria to take up and retain calcium. J Biol Chem1982;257:11558–62.
45.
FreiBWinterhalterKHRichterC. Mechanism of alloxan-induced calcium release from rat liver mitochondria. J Biol Chem1985;260:7394–7401.
46.
LinkGPinsonAKahaneIHershkoC. Iron loading modifies the fatty acid composition of cultured rat myocardial cells and liposomal vesicles: Effect of ascorbate and α-tocopherol on myocardial lipid peroxidation. J Lab Clin Med1989;114:243–9.
47.
HeysADDormandyTL. Lipid peroxidation in iron loaded spleens. Clin Sci (Lond)1981;60:295–301.
48.
O'ConnellMJWardRJBaumHPetersTJ. The role of iron in ferritin- and haemosiderin-mediated lipid peroxidation in liposomes. Biochem J1985;229:135–9.
49.
NienhuisAW. Vitamin C and iron. N Engl J Med1981;304:170–1.
50.
HershkoCLinkGPinsonA. Modification of iron uptake and lipid peroxidation by hypoxia, ascorbic acid, and α-tocopherol in iron-loaded rat myocardial cell cultures. J Lab Clin Med1987;110:355–61.
51.
MorebJHershkoCHasinY. Effects of acute iron loading on contractility and spontaneous beating rate of cultured rat myocardial cells. Basic Res Cardiol1988;83:360–8.
52.
US Food and Drug Administration. Preventing iron poisoning in children. FDA Backgrounder, 15 January 1997.
53.
CoveyTJ. Ferrous sulfate poisoning: A review, case summaries and therapeutic regimen. J Pediatr1964;64:218–26.
54.
SteinMBlayneyDFeitTGoergenTGMicikSNyhanWL. Acute iron poisoning in children. West J Med1976;125:289–97.
55.
ReynoldsLG. Diagnosis and management of acute iron poisoning. Baillieres Clin Haematol1989;2:423–33.
56.
SinghiSCBaranwalAK. Acute iron poisoning: Clinical picture, intensive care needs and outcome. Indian Pediatr2003;40:1177–82.
57.
PetoTEThompsonJ. A reappraisal of the effect of iron and desferrioxamine on the growth of Plasmodium falciparum in vitro: The unimportance of serum iron. Br J Haematol1986;63:273–80.
58.
Raventos-SuarezCPollackSNagelRL. Plasmodium falciparum: Inhibition of in vitro growth by desferrioxamine. Am J Trop Med Hyg1982;31:919–22.
59.
NyholmSMannGJJohanssonAGBergeronRJGraslundAThelanderL. Role of ribonucleotide reductase in inhibition of mammalian cell growth by potent iron chelators. J Biol Chem1993;268:26200–5.
60.
HershkoCPetoTE. Deferoxamine inhibition of malaria is independent of host iron status. J Exp Med1998;168:375–87.
61.
BienzleUFritschKGHothGRozdzinskiEKöhlerKKalinowskiMKremsnerPRosenkaimerFFeldmeierH. Inhibition of Plasmodium vinckei-malaria in mice by recombinant murine interferon-gamma. Acta Trop1988;45:289–90.
62.
YinnonAMTheanachoENGradyRWSpiraDTHershkoC. Antimalarial effect of HBED and other phenolic and catecholic iron chelators. Blood1989;74:2166–71.
63.
HeppnerDGHallawayPEKontoghiorghesGJEatonJW. Antimalarial properties of orally active iron chelators. Blood1998;72:358–61.
64.
ClarkeCJEatonJM. Hydrophobic iron chelators as new antimalarial drugs. Clin Res1990;38:300a.
65.
TsafackALoyevskyMPonkaPCabantchikZI. Mode of action of iron (III) chelators as anti-malarials. IV. Potentiation of desferal action by benzoyl and isonicotinoyl hydrazone derivatives. J Lab Clin Med1996;127:574–82.
66.
GordeukVRThumaPEBrittenhamGMZuluSSimwanzaGMhanguAFleschGParryD. Iron chelation with deferoxamine B in adults with asymptomatic Plasmodium falciparum parasitemia. Blood1992;79:308–12.
67.
GordeukVRThumaPEBrittenhamGMBiembaGZuluSSimwanzaGKalensePM'hangoAParryDPolteraAAAikawaM. Iron chelation as a chemotherapeutic strategy for falciparum malaria. Am J Trop Med Hyg1993;48:193–7.
68.
BunnagDPolteraAAViravanCLooareesuwanSHarinasutaTSchindléryC. Plasmodicidal effect of desferrioxamine B in human vivax or falciparum malaria from Thailand. Acta Trop1992;52:59–67.
69.
ThumaPEOlivieriNFMabezaGFBiembaGParryDZuluSFassosFFMcClellandRAKorenGBrittenhamGMGordeukVR. Assessment of the effect of the oral iron chelator deferiprone on mild Plasmodium falciparum parasitemia in humans. Am J Trop Med Hyg1998;58:358–64.
70.
GordeukVRThumaPEBrittenhamGMMcLarenCParryDBackenstoseARBiembaGMsiskaRHolmesLMcKinleyEVargasLGilkesonRCPolteraAA. Effect of iron chelation therapy on recovery from deep coma in children with cerebral malaria. N Engl J Med1992;327:1473–7.
71.
ThumaPEMabezaGFBiembaGBhatGJMcLarenCMoyoVMZuluSKhumaloHMabezaPM'hangoAParryDPolteraAABrittenhamGMGordeukVR. Effect of iron chelation therapy on mortality in Zambian children with cerebral malaria. Trans R Soc Trop Med Hyg1998;92:214–8.
72.
MohantyDGhoshKPathareAVKarnadD. Deferiprone (L1) as an adjuvant therapy for Plasmodium falciparum malaria. Indian J Med Res2002;115:17–21.
73.
SmithHJMeremikwuM. Iron chelating agents for treating malaria. Cochrane Database Syst Rev2003;(2):CD0014174.
74.
AikawaMWernsdorferWHMcGregorILivingstoneCEdinburgh. Fine structure of malaria parasites in the various stages of development. In: ScheibelLWShermanIW, eds. Principles and practice of malariology. Edinburgh, UK: Churchill Livingstone, 1988;97–130.
75.
SlaterAFCeramiA. Inhibition by chloroquine of a novel haem polymerase enzyme activity in malaria trophozoites. Nature1992;355:167–9.
76.
PouvelleBSpiegelRHsiaoLHowardRJMorrisRLThomasAPTaraschiTF. Direct access to serum macromolecules by intraerythrocytic malaria parasites. Nature1991;353:73–5.
77.
LoyevskyMLyttonSDMesterBLibmanJShanzerACabantchikZI. The antimalarial action of Desferal involves a direct access route to erythrocytic (Plasmodium falciparum) parasites. J Clin Invest1993;91:218–24.
78.
PollackSSchnelleV. Inability to detect transferrin receptors on P. falciparum parasitized red cells. Br J Haematol1988;68:125–9.
79.
Sanchez-LopezRHaldarK. A transferrin-independent iron uptake activity in Plasmodium falciparum-infected and uninfected erythrocytes. Mol Biochem Parasitol1992;55:9–20.
80.
GabayTGinsburgH. Haemoglobin denaturation and iron release in acidified red blood cell lysate—A possible source of iron for intraerythrocytic malaria parasites. Exp Parasitol1993;77:261–72.
81.
LoyevskyMJohnCDickensBHuVMillerJHGordeukVR. Chelation of iron within the erythrocytic Plasmodium falciparum parasite by iron chelators. Mol Biochem Parasitol1999;101:43–59.
82.
OppenheimerSJ. Iron and its relation to immunity and infectious disease. J Nutr2001;131:616S–35S.
83.
HershkoC. Iron, infection and immune function. Proc Nutr Soc1993;52:165–74.
84.
GeraTSachdevHP. Effect of iron supplementation on incidence of infectious illness in children: Systematic review. BMJ2002;325:1142.
85.
TielschJMKhatrySKStoltzfusRJKatzJLeClerqSCAdhikariRMullanyLCShrestaSBlackRE. Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: Community-based, cluster-randomised, placebo-controlled trial. Lancet2006;367:144–52.
86.
SazawalSBlackRERamsanMChwayaHMStoltzfusRJDuttaADhingraUKaboleIDebSOthmanMKKaboleFM. Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: Community-based, randomised, placebo-controlled trial. Lancet2006;367:133–43.
87.
MuleroVBrockJH. Disturbance in iron homeostasis. In: WeissGGordeukVRHershkoC, eds. Anemia of chronic disease. Boca Raton, Fla, USA: Taylor & Francis, 2005:105–26.
88.
JasonJArchibaldLKNwanyanwuOCBellMBuchananILarnedJKazembePNDobbieHParekhBByrdMGEickAHanAJarvisWR. Cytokines and malaria parasitemia. Clin Immunol2001;100:208–18.
89.
NyakerigaAMWilliamsTNMarshKWambuaSPerlmannHPerlmannPGrandienATroye-BlombergM. Cytokine mRNA expression and iron status in children living in a malaria endemic area. Scand J Immunol2005;61:370–5.
90.
NyakerigaAMTroye-BlombergMChemtaiAKMarshKWilliamsTN. Malaria and nutritional status in children living on the coast of Kenya. Am J Clin Nutr2004;80:1604–10.
