title: Local proinflammatory effects of repeated skin exposure to warfarin, an anticoagulant rodenticide in rats.
abstract: OBJECTIVE
  To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin.
  
  
  METHODS
  Rats were exposed to warfarin by applying 10 μg of warfarin-sodium to 10-12 cm(2) skin (range 0.8-1 μg per 1 cm(2)) for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application.
  
  
  RESULTS
  Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury (increased malondialdehyde, MDA, production, evident histo-morphological changes in epidermis and dermis depicting cell injury and death). Increased numbers of proliferating cell nuclear antigen (PCNA(+)) cells indicated reparative processes in injured skin. Infiltration of CD3(+) cells (T lymphocytes) along with the increased production of tumor necrosis factor-a (TNF-a) by epidermal cells from warfarin-treated skin and their co-stimulatory effect in an in vitro T-cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin.
  
  
  CONCLUSIONS
  Presented data have documented tissue damage associated with immune/inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.
authors.affiliation: Department of Ecology, University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Popov
authors.forename: Ivana
authors.initials: I
authors.lastname: Mirkov
authors.forename: Lidija
authors.initials: L
authors.lastname: Zolotarevski
authors.forename: Milena
authors.initials: M
authors.lastname: Jovic
authors.forename: Sandra
authors.initials: S
authors.lastname: Belij
authors.forename: Dragan
authors.initials: D
authors.lastname: Kataranovski
authors.forename: Milena
authors.initials: M
authors.lastname: Kataranovski
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism; D003877:Dermatitis, Contact / Q000473:pathology*; D000078404:Epidermal Cells; D005786:Gene Expression Regulation / Q000502:physiology; D007249:Inflammation / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012378:Rodenticides / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000502:physiology; D014859:Warfarin / Q000494:pharmacology*
chemical_list: D017252:CD3 Complex; D018809:Proliferating Cell Nuclear Antigen; D012378:Rodenticides; D014859:Warfarin