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 perm eability. It has been postulated that most biological activities of LPS are derived from lipid A moiety. Here we examined the effect of lipid A analog ue 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-depen dent increase in vascular permeability which was evident after 120 min. 3 ONO-4007-induced dye leakage was significantly attenuated by pretreatment s with anti-tumour necrosis factor-alpha (TNF-alpha) and anti-interleukin-1 alpha (IL-1 alpha) antibodies, but not with indomethacin (5 mg kg(-1)) or diphenhydramine (10 mg kg(-1)). ONO-4007-induced dye leakage was significan tly inhibited by a pretreatment with N-G-nitro-L-arginine methyl ester (L-N AME) (10 mg kg(-1)) but not with aminoguanidine (50 mg kg(-1)). In inducibl e nitric oxide synthase (iNOS)-deficient mice, ONO-4007 significantly incre ased the dye leakage, while ONO-4007 dilated rat thoracic aortic rings prec ontracted with phenylephrine, and the L-NAME pretreatment inhibited the dil ation. 4 Thus. TNF-alpha, IL-1 alpha and constitutive NOSs-derived nitric oxide bu t not prostaglandins or histamine play a role in ONO-4007-induced increase in vascular permeability. Although ONO-4007 mimics LPS in increasing vascul ar permeability, mechanisms of permeability change elicited by ONO-4007 wer e not identical to those of LPS.