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The cannabinoid WIN55, 212-2 abrogates dermal fibrosis in scleroderma bleomycin model
  1. Epifania Balistreri1,
  2. Estrella Garcia-Gonzalez1,
  3. Enrico Selvi1,
  4. Alfiya Akhmetshina2,
  5. Katrin Palumbo2,
  6. Sauro Lorenzini1,
  7. Roberta Maggio1,
  8. Monica Lucattelli3,
  9. Mauro Galeazzi1,
  10. Jörg W H Distler2
  1. 1Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, University of Siena, Siena, Italy
  2. 2Department of Internal Medicine 3, University of Erlangen-Nuremberg, Germany
  3. 3Department of Pathophysiology, Experimental Medicine and Public Health, University of Siena, Siena, Italy
  1. Correspondence to Enrico Selvi, Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, University of Siena, Viale Bracci 1, 53100 Siena, Italy; enrico.selvi{at}


Objectives 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.

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  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.