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mRNA Production and TNF Release
1 Department of Medicine, University of Washington, Seattle, WA, USA; Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
* To whom correspondence should be addressed. E-mail: dzager{at}fhcrc.org.
Background: IV 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
message expression and plasma TNF levels.
Methods: CD-1 mice received either IV Fe -sucrose, -gluconate, or -dextran (FeS, FeG, or FeD, respectively; 2 mg), followed by either endotoxin (LPS) or glycerol injection 0-48 hrs later. Plasma TNF was assessed by ELISA 2-3 hrs after the LPS or glycerol challenge. TNF mRNA expression (RT-PCR) was measured in kidney, heart, liver, lung, and spleen with Fe ± LPS treatment. Finally, the relative impacts of IM vs. IV Fe,
and of glutathione (GSH), on Fe / LPS- induced TNF generation were assessed.
Results: Each Fe preparation significantly enhanced LPS- or muscle injury- mediated TNF generation. This effect was observed for at least 48 hrs 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 or tissue mRNA. However, it potentiated post injury-induced TNF mRNA increments, and in an organ specific fashion (kidney, heart, and lung; but not in liver or spleen). IM administration, but not GSH treatment, negated Fe's ability to synergize LPS mediated- TNF release.
Conclusions: 1) IV Fe can enhance TNF generation during LPS- or glycerol inducedtissue
damage; 2) Increased TNF gene transcription in kidney, heart and lung may contribute to this result; and 3) IM administration, but not GSH, might potentially
mitigate some of Fe's systemic toxic effects.
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