title: Skin response to epicutaneous application of anticoagulant rodenticide warfarin is characterized by differential time- and dose-dependent changes in cell activity.
abstract: BACKGROUND
  Skin is the target of both acute and chronic exposure to warfarin, coumarin anticoagulant. Single exposure of rat skin to this agent induces early (24 h following epicutaneous administration) local response which might be part of inflammatory/reparatory homeostatic program or introduction to pathological events in exposed skin.
  
  
  OBJECTIVE
  To examine time-dependent changes in skin of rats exposed to epicutaneously applied warfarin.
  
  
  METHODS
  The effect of low (10 μg) and high (100 μg) doses of warfarin on histologically evident changes of epidermis (epidermal thickness) and dermis (numbers of mesenchymal cells and dermal capillaries), skin cell proliferative activity (Ki67(+) and PCNA(+) cells) and apoptotic (TUNEL(+)) and necrotic (ultra structural appearance) cells was examined one, three and seven days after the application.
  
  
  RESULTS
  Both warfarin doses affected the majority of skin cell activity, but with differential time-course of skin epidermal and dermal cells state/activity. The occurrence of necrotic/apoptotic epidermal and dermal cells was noted the first day after the application and the activities which point to tissue reparation/remodeling were observed seven days after skin exposure to this agent.
  
  
  CONCLUSIONS
  The observed pattern of changes (early evidence of cell/tissue injury which was later followed by signs of cell activity characteristic for tissue reparation/remodeling) implied warfarin-induced toxicity in skin cells as stimulus for subsequent activities relevant for tissue homeostasis.
  
  
  CONCLUSIONS
  The data presented provide new and additional information concerning skin responses to warfarin that gains access to this tissue.
authors.affiliation: a Military Medical Academy, Institute of Pathology , Belgrade , Serbia .
authors.forename: Lidija
authors.initials: L
authors.lastname: Zolotarevski
authors.affiliation: a Military Medical Academy, Institute of Pathology , Belgrade , Serbia .
authors.forename: Milena
authors.initials: M
authors.lastname: Jovic
authors.affiliation: b Department of Ecology , Institute for Biological Research "Sinisa Stankovic", University of Belgrade , Belgrade , Serbia , and.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Popov Aleksandrov
authors.affiliation: a Military Medical Academy, Institute of Pathology , Belgrade , Serbia .
authors.forename: Petar
authors.initials: P
authors.lastname: Milosavljevic
authors.affiliation: c Faculty of Biology , Institute of Zoology, University of Belgrade , Belgrade , Serbia.
authors.forename: Goran
authors.initials: G
authors.lastname: Brajuskovic
authors.affiliation: b Department of Ecology , Institute for Biological Research "Sinisa Stankovic", University of Belgrade , Belgrade , Serbia , and.
authors.forename: Jelena
authors.initials: J
authors.lastname: Demenesku
authors.affiliation: b Department of Ecology , Institute for Biological Research "Sinisa Stankovic", University of Belgrade , Belgrade , Serbia , and.
authors.forename: Ivana
authors.initials: I
authors.lastname: Mirkov
authors.affiliation: b Department of Ecology , Institute for Biological Research "Sinisa Stankovic", University of Belgrade , Belgrade , Serbia , and.
authors.forename: Marina
authors.initials: M
authors.lastname: Ninkov
authors.affiliation: b Department of Ecology , Institute for Biological Research "Sinisa Stankovic", University of Belgrade , Belgrade , Serbia , and.
authors.forename: Dragan
authors.initials: D
authors.lastname: Kataranovski
authors.affiliation: b Department of Ecology , Institute for Biological Research "Sinisa Stankovic", University of Belgrade , Belgrade , Serbia , and.
authors.forename: Milena
authors.initials: M
authors.lastname: Kataranovski
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000925:Anticoagulants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051381:Rats; D012378:Rodenticides / Q000633:toxicity*; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D014859:Warfarin / Q000633:toxicity*
chemical_list: D000925:Anticoagulants; D019394:Ki-67 Antigen; D018809:Proliferating Cell Nuclear Antigen; D012378:Rodenticides; D014859:Warfarin
keywords: Epicutaneous warfarin; PCNA+ and Ki67+ cells); rats; skin cell viability and proliferation (TUNEL+; skin histology