Hydrazine sulfate protection against endotoxin lethality: analysis of effects on expression of hepatic cytokine genes and an acute-phase gene.
Hydrazine sulfate (HS) pretreatment protects mice against the lethal effects of bacterial endotoxin lipopolysaccharide (LPS) through mechanisms yet to be established. The liver was examined as a model organ to determine HS effects on (a) LPS activation of leukocyte (Kupffer cell) interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) genes and (b) subsequent cytokine-mediated induction of the acute-phase response as measured by hepatic metallothionein (MT) gene expression. The utility of this model was documented by in situ hybridization which showed that acute induction by LPS of the IL-1 beta gene occurred in cells found in liver sinusoids, consistent with Kupffer cells, whereas induction of the MT gene occurred in hepatocytes. The cell specific expression of these genes was further verified by Northern blot hybridization to LPS-treated liver RNA which showed that the LPS-mediated increase in hepatic cytokine mRNA levels, unlike that of MT, was not prevented by D-galactosamine (D-GalN) treatment. Northern blot hybridization established that HS pretreatment did not block the acute induction of hepatic cytokine mRNAs (IL-1 beta and TNF-alpha) by LPS nor did it induce these cytokine mRNAs in the absence of LPS. Northern blot hybridization further established that HS did not prevent LPS-mediated activation of hepatocyte MT gene expression. Thus, HS does not prevent LPS from activating liver leukocytes. These results also suggest that HS pretreatment neither prevents the general release of cytokines from LPS activated leukocytes nor the general induction of acute-phase protein gene expression in hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
D000209:Acute-Phase Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D016207:Cytokines / Q000235:genetics*; D004731:Endotoxins / Q000633:toxicity*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006834:Hydrazines / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000235:genetics; D007962:Leukocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D000209:Acute-Phase Proteins; D016207:Cytokines; D004731:Endotoxins; D006834:Hydrazines; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C029424:hydrazine; D008668:Metallothionein