The cannabinoid WIN55,212-2 abrogates dermal fibrosis in scleroderma bleomycin model
The cannabinoid WIN55,212-2 abrogates dermal fibrosis in scleroderma bleomycin model
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DOI：
10.1136/ard.2010.137539
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发表时间：
2011-04-01
影响因子：
27.4
通讯作者：
Distler, Joerg W. H.
中科院分区：
文献类型：
--
作者：
Balistreri, Epifania;Garcia-Gonzalez, Estrella;Distler, Joerg W. H.
目的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。本研究的目的是研究的合成大麻素受体激动剂的能力，以修改皮肤纤维化的博莱霉素小鼠模型scleroderma.Methods皮肤纤维化诱导的局部注射博莱霉素在两组DBA/2 J小鼠。一组用合成大麻素WIN 55，212-2以1 mg/kg/天共处理。通过组织学和皮肤厚度和羟脯氨酸含量来评估皮肤纤维化。检查成纤维细胞活化的标志物，包括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。PSMAD 2/3的水平，这是至关重要的细胞外基质过度productions.Results博莱霉素治疗诱导典型的皮肤纤维化。在WIN 55、212-2治疗后，完全防止了真皮纤维化。皮下炎性细胞浸润、真皮厚度和胶原含量与对照组相似。合成大麻素通过强烈抑制TGF β、CTGF和PDGF-BB表达来防止博来霉素诱导的成纤维细胞活化。SMAD 2/3的磷酸化在WIN 55，212-2暴露后显著下调。结论总之，结果表明合成大麻素WIN 55，212-2能够预防硬皮病小鼠模型中的皮肤纤维化。
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 a smooth muscle actin and the profibrotic cytokines transforming growth factor (TGF)beta, 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 TGF beta, 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.