Serum complement mediates endotoxin-induced cysteinyl leukotriene formation in rats in vivo.
To investigate potential mediators responsible for cysteinyl leukotriene formation during endotoxemia, male Fischer rats received an intravenous bolus injection of 5 mg/kg Salmonella enteritidis endotoxin and cysteinyl leukotrienes were measured by gas chromatography-mass spectrometry. The biliary excretion of leukotriene (LT) C4 (0.20 +/- 0.02 pmol.min-1.g liver-1) and N-acetyl-LTE4 (0.37 +/- 0.07 pmol.min-1.g-1) was increased by 190 and 1,000%, respectively, during the first 30 min after endotoxin injection. Endotoxin also caused a temporary reduction of hepatic ATP levels by 84%. Depletion of serum complement almost completely abolished the endotoxin-induced increase of cysteinyl leukotrienes in bile without affecting the biliary excretion mechanism. Intravenous injection of activated complement factors caused cysteinyl leukotriene formation and reduced the hepatic ATP content similar to endotoxin. Depletion of glutathione in the liver prevented cysteinyl leukotriene formation and the complement-induced ATP depletion. It is concluded that endotoxin-induced cysteinyl leukotriene generation in vivo is mediated predominantly through activation of complement. The vasoconstrictive cysteinyl leukotrienes are then responsible for ATP depletion in the liver.
Jaeschke
H
H
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030.
Raftery
M J
MJ
Justesen
U
U
Gaskell
S J
SJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003165:Complement System Proteins / Q000378:metabolism / Q000502:physiology*; D004546:Elapid Venoms / Q000494:pharmacology; D004731:Endotoxins / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D007201:Indicator Dilution Techniques; D017999:Leukotriene E4 / Q000031:analogs & derivatives*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013189:SRS-A / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000378:metabolism; D012477:Salmonella enteritidis; D015054:Zymosan / Q000494:pharmacology
D004546:Elapid Venoms; D004731:Endotoxins; D013189:SRS-A; C016310:cobra venom factor; D017999:Leukotriene E4; C047630:N-acetylleukotriene E4; D000255:Adenosine Triphosphate; D003165:Complement System Proteins; D015054:Zymosan