Rheumatology Unit, Department of Clinical Medicine and Immunological Sciences, University of Siena, Viale Bracci 1, 53100 Siena, Italy.
Ann Rheum Dis. 2011 Apr;70(4):695-9. doi: 10.1136/ard.2010.137539. Epub 2010 Dec 21.
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.
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.
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.
Taken together, the results indicate that the synthetic cannabinoid WIN55,212-2 is capable of preventing skin fibrosis in a mouse model of scleroderma.
越来越多的证据表明，内源性大麻素系统可能参与病理性纤维化，其调节可能限制纤维化反应。本研究旨在研究一种合成大麻素受体激动剂对博来霉素诱导的硬皮病小鼠模型皮肤纤维化的修饰作用。
两组 DBA/2J 小鼠局部注射博来霉素诱导皮肤纤维化。一组用合成大麻素 WIN55,212-2 以 1mg/kg/天的剂量进行联合治疗。通过组织学和皮肤厚度以及羟脯氨酸含量来评估皮肤纤维化，并对成纤维细胞激活标志物，包括α平滑肌肌动蛋白和促纤维化细胞因子转化生长因子（TGF）β、结缔组织生长因子（CTGF）和血小板衍生生长因子（PDGF）-BB 进行检测。分析对细胞外基质过度产生至关重要的 PSMAD2/3 水平。
博来霉素处理诱导了典型的皮肤纤维化。WIN55,212-2 治疗完全预防了真皮纤维化。皮下炎性细胞浸润、真皮厚度和胶原含量与对照组相似。合成大麻素可预防博来霉素诱导的成纤维细胞激活，同时强烈抑制 TGFβ、CTGF 和 PDGF-BB 的表达。WIN55,212-2 暴露后 SMAD2/3 的磷酸化显著下调。
综上所述，结果表明合成大麻素 WIN55,212-2 能够预防硬皮病小鼠模型中的皮肤纤维化。
