title: Development of a mouse model for sulfur mustard-induced ocular injury and long-term clinical analysis of injury progression.
abstract: BACKGROUND
  Sulfur mustard (SM) is a highly reactive vesicating agent that can induce severe ocular injury. The clinical features of this injury have been well documented, but the molecular basis for this pathology is not well understood. Identification and validation of specific targets is necessary in the effort to develop effective therapeutics for this injury. Currently used rabbit models are not well suited for many molecular studies because the necessary reagents are not widely available. However, these reagents are widely available for the mouse model.
  
  
  OBJECTIVE
  Our objective is to develop a mouse model of SM-induced ocular injury suitable for the study of the molecular mechanisms of injury and the evaluation of therapeutics.
  
  
  METHODS
  Ocular exposure to sulfur mustard vapor was accomplished by using a vapor cup method. Dose response studies were conducted in female BALB/c mice. An exposure dose which produced moderate injury was selected for further study as moderate injury was determined to be amenable to studying the beneficial effects of potential therapeutics. Histopathology and inflammatory markers were evaluated for up to 28 days after exposure, while clinical injury progression was evaluated for 1 year post-exposure.
  
  
  RESULTS
  A biphasic ocular injury was observed in mice exposed to SM. Acute phase SM ocular injury in mice was characterized by significant corneal epithelium loss, corneal edema, limbal engorgement, and ocular inflammation. This was followed by a brief recovery phase. A delayed injury phase then ensued in the following weeks to months and was characterized by keratitis, stromal edema, infiltrates, neovascularization, and eventual corneal scarring.
  
  
  CONCLUSIONS
  SM-induced ocular injury in mice is consistent with observations of SM-induced ocular injury in humans and rabbit models. However, in the mouse model, the SM ocular injury, a more rapid onset of the delayed injury phase was observed. We have developed an animal model of SM injury that is suitable for studies to elucidate molecular mechanisms of injury and identify potential therapeutic targets.
authors.affiliation: USAMRICD, Cellular and Molecular Biology, Gunpowder 21010, USA. albert.leonard.ruff@us.army.mil
authors.forename: Albert Leonard
authors.initials: AL
authors.lastname: Ruff
authors.forename: Anthony John
authors.initials: AJ
authors.lastname: Jarecke
authors.forename: David Joseph
authors.initials: DJ
authors.lastname: Hilber
authors.forename: Christin Coleen
authors.initials: CC
authors.lastname: Rothwell
authors.forename: Sarah Lynn
authors.initials: SL
authors.lastname: Beach
authors.forename: James Franklin
authors.initials: JF
authors.lastname: Dillman
mesh_terms: D000818:Animals; D002619:Chemical Warfare Agents / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D019573:Epithelium, Corneal / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D005131:Eye Injuries / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009151:Mustard Gas / Q000633:toxicity*; D018919:Neovascularization, Physiologic; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D002619:Chemical Warfare Agents; D016207:Cytokines; D019010:Vascular Cell Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D009151:Mustard Gas