Role of inflammatory mediators in lipid A analogue (ONO-4007)-induced vascular permeability change in mouse skin.
1. Endotoxin shock is accompanied by an increase in peripheral vascular permeability. It has been postulated that most biological activities of LPS are derived from lipid A moiety. Here we examined the effect of lipid A analogue ONO-4007 in increasing vascular permeability and the possible mediators in mouse skin by a dye leakage method. 2. Subcutaneous injection of ONO-4007 (1 - 2 mg site(-1)) induced a dose-dependent increase in vascular permeability which was evident after 120 min. 3. ONO-4007-induced dye leakage was significantly attenuated by pretreatments with anti-tumour necrosis factor-alpha (TNF-alpha) and anti-interleukin-1alpha (IL-1alpha) antibodies, but not with indomethacin (5 mg kg(-1)) or diphenhydramine (10 mg kg(-1)). ONO-4007-induced dye leakage was significantly inhibited by a pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) (10 mg kg(-1)) but not with aminoguanidine (50 mg kg(-1)). In inducible nitric oxide synthase (iNOS)-deficient mice, ONO-4007 significantly increased the dye leakage, while ONO-4007 dilated rat thoracic aortic rings pre-contracted with phenylephrine, and the L-NAME pretreatment inhibited the dilation. 4. Thus, TNF-alpha, IL-1alpha and constitutive NOSs-derived nitric oxide but not prostaglandins or histamine play a role in ONO-4007-induced increase in vascular permeability. Although ONO-4007 mimics LPS in increasing vascular permeability, mechanisms of permeability change elicited by ONO-4007 were not identical to those of LPS.
Ishida
H
H
Department of Anesthesiology, Nippon Medical School, Tokyo, Japan. hiro-i@research.twmu.ac.jp
Fujii
E
E
Irie
K
K
Yoshioka
T
T
Muraki
T
T
Ogawa
R
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001391:Azo Compounds / Q000493:pharmacokinetics; D002199:Capillary Permeability / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000276:immunology / Q000502:physiology*; D007375:Interleukin-1 / Q000276:immunology / Q000502:physiology; D008050:Lipid A / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D019001:Nitric Oxide Synthase / Q000172:deficiency; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D012867:Skin / Q000098:blood supply / Q000187:drug effects*; D013997:Time Factors; D014343:Trypan Blue; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
D000911:Antibodies, Monoclonal; D001391:Azo Compounds; D018836:Inflammation Mediators; D007375:Interleukin-1; D008050:Lipid A; C086889:ONO 4007; D014409:Tumor Necrosis Factor-alpha; C009000:pontamine sky blue; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D014343:Trypan Blue