title: The cannabinoid WIN55, 212-2 abrogates dermal fibrosis in scleroderma bleomycin model.
abstract: OBJECTIVE
  There is increasing evidence that the endocannabinoid system may be involved in pathological fibrosis, and that its modulation might limit fibrotic responses. The aim of this study was to examine the capacity of a synthetic cannabinoid receptor agonist to modify skin fibrosis in the bleomycin mouse model of scleroderma.
  
  
  METHODS
  Skin fibrosis was induced by local injections of bleomycin in two groups of DBA/2J mice. One group was cotreated with the synthetic cannabinoid WIN55,212-2 at 1 mg/kg/day. Skin fibrosis was evaluated by histology and skin thickness and hydroxyproline content were quantified. Markers of fibroblast activation, including α smooth muscle actin and the profibrotic cytokines transforming growth factor (TGF)β, connective tissue growth factor (CTGF) and platelet-derived growth factor (PDGF)-BB, were examined. Levels of PSMAD2/3, which are crucial in extracellular matrix overproduction, were analysed.
  
  
  RESULTS
  Bleomycin treatment induced typical skin fibrosis. Upon WIN55,212-2 treatment dermal fibrosis was completely prevented. Subcutaneous inflammatory cell infiltration, dermal thickness and collagen content resulted similar to those of the control group. The synthetic cannabinoid prevented fibroblasts activation induced by bleomycin, paralleled by a strong inhibition of TGFβ, CTGF and PDGF-BB expression. Phosphorylation of SMAD2/3 was significantly downregulated after WIN55,212-2 exposure.
  
  
  CONCLUSIONS
  Taken together, the results indicate that the synthetic cannabinoid WIN55,212-2 is capable of preventing skin fibrosis in a mouse model of scleroderma.
authors.affiliation: Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, University of Siena, Viale Bracci 1, 53100 Siena, Italy.
authors.forename: Epifania
authors.initials: E
authors.lastname: Balistreri
authors.forename: Estrella
authors.initials: E
authors.lastname: Garcia-Gonzalez
authors.forename: Enrico
authors.initials: E
authors.lastname: Selvi
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Sauro
authors.initials: S
authors.lastname: Lorenzini
authors.forename: Roberta
authors.initials: R
authors.lastname: Maggio
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.forename: Mauro
authors.initials: M
authors.lastname: Galeazzi
authors.forename: Jörg W H
authors.initials: JW
authors.lastname: Distler
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000627:therapeutic use*; D001761:Bleomycin; D003879:Dermatologic Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D051379:Mice; D008811:Mice, Inbred DBA; D009025:Morpholines / Q000627:therapeutic use*; D009281:Naphthalenes / Q000627:therapeutic use*; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: D048588:Benzoxazines; D003879:Dermatologic Agents; D009025:Morpholines; D009281:Naphthalenes; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; C075278:platelet-derived growth factor A; D001761:Bleomycin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone