title: Time course of skin features and inflammatory biomarkers after liquid sulfur mustard exposure in SKH-1 hairless mice.
abstract: Sulfur mustard (SM) is a strong bifunctional alkylating agent that produces severe tissue injuries characterized by erythema, edema, subepidermal blisters and a delayed inflammatory response after cutaneous exposure. However, despite its long history, SM remains a threat because of the lack of effective medical countermeasures as the molecular mechanisms of these events remain unclear. This limited number of therapeutic options results in part of an absence of appropriate animal models. We propose here to use SKH-1 hairless mouse as the appropriate model for the design of therapeutic strategies against SM-induced skin toxicity. In the present study particular emphasis was placed on histopathological changes associated with inflammatory responses after topical exposure of dorsal skin to three different doses of SM (0.6, 6 and 60mg/kg) corresponding to a superficial, a second-degree and a third-degree burn. Firstly, clinical evaluation of SM-induced skin lesions using non invasive bioengineering methods showed that erythema and impairment of skin barrier increased in a dose-dependent manner. Histological evaluation of skin sections exposed to SM revealed that the time to onset and the severity of symptoms including disorganization of epidermal basal cells, number of pyknotic nuclei, activation of mast cells and neutrophils dermal invasion were dose-dependent. These histopathological changes were associated with a dose- and time-dependent increase in expression of specific mRNA for inflammatory mediators such as interleukins (IL1β and IL6), tumor necrosis factor (TNF)-α, cycloxygenase-2 (COX-2), macrophage inflammatory proteins (MIP-1α, MIP-2 and MIP-1αR) and keratinocyte chemoattractant (KC also called CXCL1) as well as adhesion molecules (L-selectin and vascular cell adhesion molecule (VCAM)) and growth factor (granulocyte colony-stimulating factor (Csf3)). A dose-dependent increase was also noted after SM exposure for mRNA of matrix metalloproteinases (MMP9) and laminin-γ2 which are associated with SM-induced blisters formation. Taken together, our results show that SM-induced skin histopathological changes related to inflammation is similar in SKH-1 hairless mice and humans. SKH-1 mouse is thus a reliable animal model for investigating the SM-induced skin toxicity and to develop efficient treatment against SM-induced inflammatory skin lesions.
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France. Electronic address: stephane.mouret@irba.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mouret
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wartelle
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France; UJF & CNRS, CEA, INAC, SCIB, LCIB (UMR_E 3CEA-UJF), Laboratoire Lésions des Acides Nucléiques, 17 Rue des Martyrs, Grenoble Cedex 9 F-38054, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Batal
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: Sandy
authors.initials: S
authors.lastname: Emorine
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Bertoni
authors.affiliation: Pôle de Génomique, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Poyot
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Cléry-Barraud
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: Nacera El
authors.initials: NE
authors.lastname: Bakdouri
authors.affiliation: Pôle de Génomique, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: André
authors.initials: A
authors.lastname: Peinnequin
authors.affiliation: UJF & CNRS, CEA, INAC, SCIB, LCIB (UMR_E 3CEA-UJF), Laboratoire Lésions des Acides Nucléiques, 17 Rue des Martyrs, Grenoble Cedex 9 F-38054, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Douki
authors.affiliation: Unité Brûlure Chimique, Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, 24 avenue Maquis du Grésivaudan, 38700 La Tronche, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boudry
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002057:Burns, Chemical / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015550:Cell Degranulation; D002619:Chemical Warfare Agents; D003877:Dermatitis, Contact / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008812:Mice, Hairless; D009151:Mustard Gas; D009504:Neutrophils / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
chemical_list: D015415:Biomarkers; D002619:Chemical Warfare Agents; D018836:Inflammation Mediators; C498522:Lamc2 protein, mouse; D007797:Laminin; D012333:RNA, Messenger; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D009151:Mustard Gas
keywords: Mast cells; Matrix metalloproteinases; SKH-1 hairless mice; Skin inflammation; Sulfur mustard; TEWL