Inhibition of endotoxin-induced hypothermia and serum TNF-alpha levels in CD-1 mice by various pharmacological agents.
Intraperitoneal injection of lipopolysaccharide (LPS) was used to elicit a sublethal, shock-like condition in mice. LPS, 2.5 mg/kg i.p., induced hypothermia, elevated serum TNF-alpha levels and lethality over a 48 h period in male CD-1 mice. The 5-lipoxygenase (LO) inhibitors, WY-50,295 tromethamine and zileuton (100 mg/kg p.o), significantly inhibited hypothermia at 4, 24 and 48 h after LPS. Interestingly, whereas cyclooxygenase (CO) inhibitors (ibuprofen, etodolac, naproxen and tenidap) at 40-80 mg/kg p.o. stimulated hypothermia at 4 h, they significantly reduced the later stages of hypothermia at 24-48 h. Rolipram (PDE-IV inhibitor) and dexamethasone significantly reduced hypothermia at 4-24 h and 1-24 h, respectively. All the anti-inflammatory agents significantly reduced elevated TNF-alpha levels at approximately 70 min post-LPS, except for ibuprofen. In conclusion, these anti-inflammatory standards indicate that LPS-induced shock involves multiple lipid mediators (PG's, LT's and possibly PAF) and secondary cytokine generation. This sublethal model of LPS-induced shock represents a sensitive model for estimating the efficacy of potential drug candidates for the treatment of endotoxic shock.
Ochalski
S J
SJ
Wyeth-Ayerst Research, Princeton, NJ 08543-8000.
Hartman
D A
DA
Belfast
M T
MT
Walter
T L
TL
Glaser
K B
KB
Carlson
R P
RP
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004731:Endotoxins / Q000633:toxicity; D006918:Hydroxyurea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D007035:Hypothermia / Q000188:drug therapy* / Q000209:etiology; D008070:Lipopolysaccharides / Q000633:toxicity; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D009280:Naphthaleneacetic Acids / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy*; D014325:Tromethamine / Q000494:pharmacology / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D008070:Lipopolysaccharides; D016859:Lipoxygenase Inhibitors; D009280:Naphthaleneacetic Acids; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D014325:Tromethamine; C067525:S(alpha)-methyl-6-(2-quinolinylmethoxy)-2-naphthaleneacetic acid; C063449:zileuton; D006918:Hydroxyurea