Tolerance to lipopolysaccharide-induced increase in vascular permeability in mouse skin.
We investigated whether tolerance develops to the lipopolysaccharide-induced increase in vascular permeability of mouse skin on pretreatment with Salmonella typhimurium lipopolysaccharide. Lipopolysaccharide-induced plasma extravasation was assessed by determining Pontamine sky blue dye accumulation in the skin where lipopolysaccharide was injected s.c. 2 h previously. When mice were pretreated with lipopolysaccharide (0.15 mg/kg i.p.), the dye leakage induced by s.c. challenge with lipopolysaccharide (400 micrograms/site) was significantly, inhibited for 2-24 h after pretreatment, indicating the development of lipopolysaccharide tolerance. At 4 h after lipopolysaccharide (0.15 mg/kg i.p.), the dose-response curve of dye leakage against the challenge dose of lipopolysaccharide shifted about 2-fold to the higher dose. The dye leakage induced by lipopolysaccharide was inhibited by pretreatment with lipopolysaccharide in a dose-dependent manner (0.05-0.15 mg/kg i.p.). Lipopolysaccharide tolerance was not seen in adrenalectomized mice. When mice were pretreated with lipopolysaccharide and NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, at the same time, the hyporesponsiveness to lipopolysaccharide challenge disappeared. However, L-NAME was ineffective to inhibit the development of lipopolysaccharide tolerance when administered 24 h after lipopolysaccharide pretreatment or just before the lipopolysaccharide challenge. Tumor necrosis factor-alpha and interleukin-1 alpha but not interleukin-6 induced a similar hyporesponsiveness to lipopolysaccharide. These results suggest that tolerance develops to the lipopolysaccharide-induced increase in vascular permeability in mouse skin after a single lipopolysaccharide administration and that endogenous glucocorticoids and NO are necessary for induction of lipopolysaccharide tolerance. Hyporesponsiveness induced by lipopolysaccharide pretreatment may be mediated by production of some cytokines such as tumor necrosis factor-alpha or interleukin-1 alpha.
Department of Pharmacology, Tokyo Women's Medical College, Japan.
E
E
Fujii
K
K
Irie
Y
Y
Uchida
F
F
Tsukahara
K
K
Ohba
A
A
Ogawa
T
T
Muraki
D000818:Animals; D001391:Azo Compounds / Q000037:antagonists & inhibitors; D001794:Blood Pressure / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects*; D004396:Coloring Agents; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D012486:Salmonella typhimurium; D012867:Skin / Q000098:blood supply* / Q000187:drug effects; D014343:Trypan Blue; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D001391:Azo Compounds; D004396:Coloring Agents; D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C009000:pontamine sky blue; D014343:Trypan Blue; D019331:NG-Nitroarginine Methyl Ester