Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis
Synthetic cannabinoid ajulemic acid exerts potent antifibrotic effects in experimental models of systemic sclerosis
复制标题
DOI：
10.1136/annrheumdis-2011-200314
复制
发表时间：
2012-09-01
影响因子：
27.4
通讯作者：
Distler, Joerg H. W.
中科院分区：
文献类型：
--
作者：
Gonzalez, Estrella Garcia;Selvi, Enrico;Distler, Joerg H. W.
背景大麻素调节硬皮病的纤维形成。Ajulemic acid（AjA）是四氢大麻酚的非精神活性合成类似物，其可以结合过氧化物酶体增殖物激活受体-γ（PPAR-gamma）。最近的证据表明，PPAR-gamma在fibrogenes.Objective的关键作用，以确定是否AjA可以调节在硬皮病小鼠模型fibrogenes.Material和方法博莱霉素诱导的实验性纤维化，以评估AjA在体内的抗纤维化作用。此外，在博来霉素诱导的皮肤纤维化的改良模型和过表达组成型活性转化生长因子β（TGF β）受体I的小鼠中分析了AjA在预先建立的纤维化中的疗效。通过定量皮肤厚度和羟脯氨酸含量来评价皮肤纤维化。作为成纤维细胞活化的标志物，检查α-平滑肌肌动蛋白。为了研究AjA在胶原蛋白新合成中的直接作用，用增加浓度的AjA处理来自硬皮病患者的皮肤成纤维细胞。蛋白质表达的PPAR-gamma，其内源性配体15 d-PGJ 2，和TGF β进行了评估之前和之后AjA treatment.Results AjA显着防止实验博莱霉素诱导的真皮纤维化和适度减少其进展时，开始3周的疾病。AjA强烈减少胶原蛋白的新合成硬皮病成纤维细胞在体外，一个行动，这是完全逆转的共同治疗与选择性PPAR-gamma antagonist.Conclusions AjA防止在体内纤维化的进展，并抑制体外纤维化通过刺激PPAR-gamma信号。由于治疗剂量的AjA在人体中耐受良好，因此建议AjA作为一种有趣的分子靶向硬皮病患者的纤维化。
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-gamma (PPAR-gamma). Recent evidence suggests a key role for PPAR-gamma in fibrogenesis.Objective To determine whether AjA can modulate fibrogenesis in murine models of scleroderma.Material and 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 beta (TGF beta) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, alpha-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-gamma, and its endogenous ligand 15d-PGJ2, and TGF beta 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-gamma antagonist.Conclusions AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-gamma 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.