Pluronic F 127 liquid sensitizes mice to low doses of Escherichia coli lipopolysaccharide.
METHODS
In murine models of endotoxemia, large amounts of lipopolysaccharide have to be administered to induce mortality. If mice are pretreated with D-galactosamine, the amount of lipopolysaccharide required to induce mortality is significantly lowered. Pluronic F 127 liquid is a relatively non-toxic copolymer that exhibits reverse gelation properties. Thus, it is a liquid at cold temperature and a gel at body temperature. The present studies were performed to ascertain whether the reverse gelation properties of Pluronic F 127 liquid could be used in devising a model of septic shock where a sustained delivery of lipopolysaccharide occurred. In evaluating this model, dose-response studies were conducted with lipopolysaccharide when a) it was administered intraperitoneally in saline or in Pluronic F 127 liquid, and b) it was administered intravenously to mice that had been pretreated with saline or Pluronic F 127 liquid. Mortality was followed for up to 72 hrs.


RESULTS
Various doses of Escherichia coli lipopolysaccharide dissolved in saline or in Pluronic F 127 liquid were administered intraperitoneally to mice. The lethal dose of lipopolysaccharide required to kill 50% of the mice (LD50) administered in Pluronic F 127 liquid was approximately ten- to 15-fold less than the values obtained for lipopolysaccharide administered in saline. This decrease in the LD50 of lipopolysaccharide was also observed if the mice were treated intraperitoneally with Pluronic F 127 liquid and challenged 6 hrs later with iv lipopolysaccharide. The concentrations of tumor necrosis factor and interleukin-6 in the plasma were significantly higher when a low dose of lipopolysaccharide was administered to mice that had been pretreated with Pluronic F 127 liquid. While there was no effect on the liver enzymes, Pluronic F 127 liquid caused an increase in the plasma triglycerides.


CONCLUSIONS
The data reported in this paper indicate that the LD50 of lipopolysaccharide is significantly decreased if it is administered in Pluronic F 127 liquid or administered to mice that have been pretreated with the Pluronic F 127 liquid. Thus, Pluronic F 127 liquid appears to sensitize mice to low levels of lipopolysaccharide. Unlike the D-galactosamine model, lipopolysaccharide can be administered as late as 6 hrs after treatment with Pluronic F 127 liquid. While the mechanisms by which Pluronic F 127 liquid sensitizes mice is not known, plasma triglycerides were increased in mice treated with this agent, suggesting that tissues responsible for the synthesis and/or degradation of triglycerides play a role in this sensitization process.
Pickett
W C
WC
Oncology, Immunology, and Formulations Research Section, American Cyanamid, Lederle Laboratories, Pearl River, NY 10965.
Torley
L W
LW
Dejoy
S Q
SQ
Gibbons
J J
JJ
Desai
N R
NR
Oronsky
A L
AL
Kerwar
S S
SS
D000818:Animals; D001831:Body Temperature; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000276:immunology*; D005069:Evaluation Studies as Topic; D007114:Immunization; D007274:Injections, Intraperitoneal; D015850:Interleukin-6 / Q000097:blood; D007928:Lethal Dose 50; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology; D008111:Liver Function Tests; D051379:Mice; D008807:Mice, Inbred BALB C; D011060:Poloxalene / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D012772:Shock, Septic / Q000097:blood / Q000276:immunology* / Q000401:mortality; D012965:Sodium Chloride / Q000008:administration & dosage; D013696:Temperature; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry
D015850:Interleukin-6; D008070:Lipopolysaccharides; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D012965:Sodium Chloride; D011060:Poloxalene