title: Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis.
abstract: BACKGROUND
  Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis.
  
  
  OBJECTIVE
  To determine whether AjA can modulate fibrogenesis in murine models of scleroderma.
  
  
  METHODS
  Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment.
  
  
  RESULTS
  AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist.
  
  
  CONCLUSIONS
  AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.
authors.affiliation: Correspondence to Estrella Garcia Gonzalez, Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, Siena 53100, Italy. estre79@gmail.com
authors.forename: Estrella Garcia
authors.initials: EG
authors.lastname: Gonzalez
authors.forename: Enrico
authors.initials: E
authors.lastname: Selvi
authors.forename: Epifania
authors.initials: E
authors.lastname: Balistreri
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: Pietro Enea
authors.initials: PE
authors.lastname: Lazzerini
authors.forename: Cinzia
authors.initials: C
authors.lastname: Montilli
authors.forename: Pier Leopoldo
authors.initials: PL
authors.lastname: Capecchi
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.forename: Caterina
authors.initials: C
authors.lastname: Baldi
authors.forename: Elena
authors.initials: E
authors.lastname: Gianchecchi
authors.forename: Mauro
authors.initials: M
authors.lastname: Galeazzi
authors.forename: Franco Laghi
authors.initials: FL
authors.lastname: Pasini
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005355:Fibrosis / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000188:drug therapy*
chemical_list: D002186:Cannabinoids; D013759:Dronabinol; D003094:Collagen; C471849:lenabasum