Changes in function of iron-loaded alveolar macrophages after in vivo administration of desferrioxamine and/or chloroquine.
Both desferrioxamine (DFO) and chloroquine can significantly reduce hepatic iron in experimental animals with iron overload by chelating iron from the low-molecular-weight pool or decreasing iron uptake by the transferrin-transferrin receptor cycle, respectively. However, no previous studies have investigated whether combination therapy of these two drugs would further decrease the tissue iron overload as well as iron-induced toxicity. Chloroquine administration, 15 mg/kg, 5x/week, to rats during the iron loading regime, 10 mg/kg, 3x/week for 4 weeks, significantly decreased both hepatic (54%) and macrophage iron content (24%). However when administered in combination with desferrioxamine, 10 mg/kg, 3x/week for 2 weeks at the cessation of iron loading, no further reduction of hepatic iron content was noted while the iron content of the macrophages significantly increased, possibly indicating the flux of ferrioxamine through these cells. Further studies are warranted to investigate the speciation of iron within these macrophages. Macrophages isolated from chloroquine-treated iron loaded rats showed a reduction in latent NFkappaB activation and a significant increase in lipopolysaccharide-stimulated nitrite release by comparison to these parameters in iron loaded macrophages. Co-administration of chloroquine and desferrioxamine normalised the latent activity of NFkappaB to that of control macrophages as well as increasing LPS-stimulated NO release towards control values. However, DFO alone did not have any significant effect upon either of these parameters. Such results may have important relevance for the reduced immune function of iron loaded macrophages isolated from thalassaemia patients receiving chelation therapy and their propensity to increased infection.
Legssyer
Rachida
R
Unite de Biochimie, Catholique University of Louvain, Batiment Lavioisier, Place Louis Pasteur 1, 1348, Louvain-la-Neuve, Belgium.
Josse
Claire
C
Piette
Jacques
J
Ward
Roberta J
RJ
Crichton
Robert R
RR
D000818:Animals; D002738:Chloroquine / Q000008:administration & dosage*; D003676:Deferoxamine / Q000008:administration & dosage*; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000378:metabolism
D009569:Nitric Oxide; D002738:Chloroquine; D007501:Iron; D003676:Deferoxamine