title: Inflammatory pathogenesis of snake venom metalloproteinase-induced skin necrosis.
abstract: Local tissue damage, characterized by edema, hemorrhage and necrosis, is a common consequence of envenoming by many vipers. We have investigated the contribution of inflammatory responses induced by the venom metalloproteinase jararhagin (isolated from Bothrops jararaca venom) in the development of these lesions. Local venom effects (edema, hemorrhage and necrosis) were induced experimentally in knockout mice deficient in the TNF receptors TNFR1 or TNFR2, IL-1betaR, IL-6 and iNOS. Jararhagin-induced dermal necrosis was abolished in mice deficient in the TNF receptors TNFR1 and TNFR2, and the same activity was significantly reduced in IL-6(-/-) mice. There was no significant difference in edema and hemorrhage activities following jararhagin insult between knockout and WT strains, indicating that these local venom metalloproteinase-induced effects are independent of these pro-inflammatory mediators. The contribution of both TNF receptors and IL-6 in local tissue necrosis raises important therapeutic issues regarding the treatment of local envenoming.
authors.affiliation: Alistair Reid Venom Research Unit, Liverpool School of Tropical Medicine, Liverpool, GB. gavin.laing@liverpool.ac.uk
authors.forename: Gavin David
authors.initials: GD
authors.lastname: Laing
authors.forename: Patricia Bianca
authors.initials: PB
authors.lastname: Clissa
authors.forename: Robert David Geoffrey
authors.initials: RD
authors.lastname: Theakston
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Moura-da-Silva
authors.forename: Mark John
authors.initials: MJ
authors.lastname: Taylor
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D003435:Crotalid Venoms / Q000633:toxicity*; D016207:Cytokines / Q000096:biosynthesis; D004487:Edema / Q000209:etiology; D006470:Hemorrhage / Q000209:etiology; D007249:Inflammation / Q000209:etiology*; D008666:Metalloendopeptidases / Q000633:toxicity*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009336:Necrosis; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D012867:Skin / Q000473:pathology*; D000097146:Bothrops jararaca Venom
chemical_list: D015703:Antigens, CD; D003435:Crotalid Venoms; D016207:Cytokines; D008666:Metalloendopeptidases; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D000097146:Bothrops jararaca Venom