Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts
Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts
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DOI：
10.1093/rheumatology/kep189
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发表时间：
2009-09-01
期刊：
影响因子：
5.5
通讯作者：
Galeazzi, Mauro
中科院分区：
文献类型：
--
作者：
Garcia-Gonzalez, Estrella;Selvi, Enrico;Galeazzi, Mauro
目标。已有研究表明，内源性大麻素系统在病理性纤维化中表达上调，而大麻素受体的调节可能会限制不受控制的纤维化的进展。本研究的目的是探讨人工合成的大麻素受体激动剂WIN55,212-2在体外大鼠肝纤维化模型中是否具有调节纤维化形成的作用。检测大麻素受体CB1和CB2在dcSSc成纤维细胞和健康对照成纤维细胞中的表达。为了研究WIN55、212-2在dcSSc纤维化形成中的作用，我们研究了在不断增加浓度的合成大麻素处理前后，I型胶原、促纤维化细胞因子、成纤维细胞向肌成纤维细胞的转分化、细胞凋亡过程和细胞外信号相关激酶1/2通路的激活。与正常对照组相比，DcSSc成纤维细胞CB1和CB2受体均高表达。WIN55,212-2导致细胞外基质沉积减少，并抑制硬皮病成纤维细胞的几种行为异常，包括转分化为肌成纤维细胞和抗凋亡。结论选择性大麻素拮抗剂不能逆转WIN55、212-2的抗纤维化作用。我们的初步发现表明，大麻素具有抗纤维化活性，因此可能代表了一类新的针对纤维化疾病的药物。
Objective. It has been demonstrated that the endocannabinoid system is up-regulated in pathologic fibrosis and that modulation of the cannabinoid receptors might limit the progression of uncontrolled fibrogenesis. The aim of this study was to investigate whether the synthetic cannabinoid receptor agonist WIN55,212-2 could modulate fibrogenesis in an in vitro model of dcSSc.Methods. The expression of cannabinoid receptors CB1 and CB2 was assessed in dcSSc fibroblasts and healthy control fibroblasts. To investigate the effect of WIN55,212-2 on dcSSc fibrogenesis, we studied type I collagen, profibrotic cytokines, fibroblast transdifferentiation into myofibroblasts, apoptotic processes and activation of the extracellular signal-related kinase 1/2 pathway prior to and after the treatment with the synthetic cannabinoid at increasing concentrations.Results. Both CB1 and CB2 receptors were over-expressed in dcSSc fibroblasts compared with healthy controls. WIN55,212-2 caused a reduction in extracellular matrix deposition and counteracted several behavioural abnormalities of scleroderma fibroblasts including transdifferentiation into myofibroblasts and resistance to apoptosis. The anti-fibrogenic effect of WIN55,212-2 was not reverted by selective cannabinoid antagonists.Conclusions. Our preliminary findings suggest that cannabinoids are provided with an anti-fibrotic activity, thereby possibly representing a new class of agents targeting fibrosis diseases.