Parenteral iron compounds sensitize mice to injury-initiated TNF-α mRNA production and TNF-α release

Abstract

Intravenous Fe is widely used to treat anemia in renal disease patients. However, concerns of potential Fe toxicity exist. To more fully define its spectrum, this study tested Fe's impact on systemic inflammation following either endotoxemia or the induction of direct tissue damage (glycerol-mediated rhabdomyolysis). The inflammatory response was gauged by tissue TNF-α message expression and plasma TNF-α levels. CD-1 mice received either intravenous Fe sucrose, -gluconate, or -dextran (FeS, FeG, or FeD, respectively; 2 mg), followed by either endotoxin (LPS) or glycerol injection 0–48 h later. Plasma TNF-α was assessed by ELISA 2–3 h after the LPS or glycerol challenge. TNF-α mRNA expression (RT-PCR) was measured in the kidney, heart, liver, lung, and spleen with Fe ± LPS treatment. Finally, the relative impacts of intramuscular vs. intravenous Fe and of glutathione (GSH) on Fe/LPS- induced TNF-α generation were assessed. Each Fe preparation significantly enhanced LPS- or muscle injury-mediated TNF-α generation. This effect was observed for at least 48 h post-Fe injection, a time at which plasma iron levels were increased by levels insufficient to fully saturate transferrin. Fe did not independently increase plasma TNF-α or tissue mRNA. However, it potentiated postinjury-induced TNF-α mRNA increments and did so in an organ-specific fashion (kidney, heart, and lung; but not in liver or spleen). Intramuscular administration, but not GSH treatment, negated Fe's ability to synergize LPS-mediated TNF-α release. We conclude 1) intravenous Fe can enhance TNF-α generation during LPS- or glycerol-induced tissue damage; 2) increased TNF-α gene transcription in the kidney, heart, and lung may contribute to this result; and 3) intramuscular administration, but not GSH, might potentially mitigate some of Fe's systemic toxic effects.