title: Role of inflammatory mediators in lipid A analogue (ONO-4007)-induced vascular permeability change in mouse skin.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Nippon Medical School, Tokyo, Japan. hiro-i@research.twmu.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Ishida
authors.forename: E
authors.initials: E
authors.lastname: Fujii
authors.forename: K
authors.initials: K
authors.lastname: Irie
authors.forename: T
authors.initials: T
authors.lastname: Yoshioka
authors.forename: T
authors.initials: T
authors.lastname: Muraki
authors.forename: R
authors.initials: R
authors.lastname: Ogawa
mesh_terms: 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
chemical_list: 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