Štorkánová Hana, Štorkánová Lenka, Navrátilová Adéla, Bečvář Viktor, Hulejová Hana, Oreská Sabína, Heřmánková Barbora, Špiritović Maja, Bečvář Radim, Pavelka Karel, Vencovský Jiří, Distler Jörg H W, Šenolt Ladislav, Tomčík Michal
Institute of Rheumatology, 12800 Prague, Czech Republic.
Department of Rheumatology, First Faculty of Medicine, Charles University, 12800 Prague, Czech Republic.
Biomedicines. 2021 Jun 7;9(6):650. doi: 10.3390/biomedicines9060650.
Our previous study demonstrated that heat shock protein 90 (Hsp90) is overexpressed in the involved skin of patients with systemic sclerosis (SSc) and in experimental dermal fibrosis. Pharmacological inhibition of Hsp90 prevented the stimulatory effects of transforming growth factor-beta on collagen synthesis and the development of dermal fibrosis in three preclinical models of SSc. In the next step of the preclinical analysis, herein, we aimed to evaluate the efficacy of an Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in the treatment of established experimental dermal fibrosis induced by bleomycin. Treatment with 17-DMAG demonstrated potent antifibrotic and anti-inflammatory properties: it decreased dermal thickening, collagen content, myofibroblast count, expression of transforming growth factor beta receptors, and pSmad3-positive cell counts, as well as leukocyte infiltration and systemic levels of crucial cytokines/chemokines involved in the pathogenesis of SSc, compared to vehicle-treated mice. 17-DMAG effectively prevented further progression and may induce regression of established bleomycin-induced dermal fibrosis to an extent comparable to nintedanib. These findings provide further evidence of the vital role of Hsp90 in the pathophysiology of SSc and characterize it as a potential target for the treatment of fibrosis with translational implications due to the availability of several Hsp90 inhibitors in clinical trials for other indications.
我们之前的研究表明，热休克蛋白90（Hsp90）在系统性硬化症（SSc）患者受累皮肤以及实验性皮肤纤维化中过表达。在SSc的三种临床前模型中，对Hsp90进行药理抑制可防止转化生长因子-β对胶原蛋白合成的刺激作用以及皮肤纤维化的发展。在临床前分析的下一步中，我们旨在评估Hsp90抑制剂17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素（17-DMAG）对已建立的博来霉素诱导的实验性皮肤纤维化的治疗效果。用17-DMAG治疗显示出强大的抗纤维化和抗炎特性：与用赋形剂处理的小鼠相比，它可减少皮肤增厚、胶原蛋白含量、肌成纤维细胞计数、转化生长因子β受体的表达以及pSmad3阳性细胞计数，同时减少白细胞浸润和参与SSc发病机制的关键细胞因子/趋化因子的全身水平。17-DMAG有效防止了疾病的进一步进展，并可能在一定程度上诱导已建立的博来霉素诱导的皮肤纤维化消退，其程度与尼达尼布相当。这些发现进一步证明了Hsp90在SSc病理生理学中的重要作用，并将其确定为治疗纤维化的潜在靶点，由于在其他适应症的临床试验中有几种Hsp90抑制剂可用，因此具有转化意义。
