Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis
Stimulation of soluble guanylate cyclase reduces experimental dermal fibrosis
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DOI：
10.1136/annrheumdis-2011-200862
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发表时间：
2012-06-01
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：
Beyer, Christian;Reich, Nicole;Distler, Joerg H. W.
背景：纤维化和血管病变是系统性硬化症(SSC)的主要特征。可溶性鸟苷环化酶激动剂(SGC)是目前正在进行的治疗肺动脉高压的Ⅲ期临床试验中的血管活性药物。目的研究sGC刺激剂的抗纤维化作用。此外，还研究了Bay41-2272对博莱霉素性皮肤纤维化和TSK-1小鼠皮肤纤维化的预防和消退作用。结果BAY 41-2272刺激SGC可剂量依赖性地抑制SSc患者和健康人真皮成纤维细胞胶原蛋白的释放。此外，BAY 41-2272还可阻止博莱霉素诱导的TSK-1小鼠皮肤纤维化和皮肤纤维化的发展，防止真皮和皮下增厚，减少肌成纤维细胞的数量，降低羟脯氨酸含量。此外，在改进的博莱霉素诱导的皮肤纤维化模型和TSK-1小鼠中，Bay 41-2272对已建立的纤维化具有高效的治疗作用。SGC刺激剂治疗耐受性良好。BAY 41-2272的相应抗肝纤维化剂量对小鼠的全身血压和心率无明显影响。结论SGC刺激剂对不同的SSC动物模型具有较强的抗肝纤维化作用和良好的耐受性。鉴于其潜在的血管活性特性，sGC刺激剂可能成为SSc纤维化和血管疾病双重治疗的候选药物。
Background Fibrosis and vascular disease are cardinal features of systemic sclerosis (SSc). Stimulators of soluble guanylate cyclase (sGC) are vasoactive drugs that are currently being evaluated in phase III clinical trials for pulmonary arterial hypertension.Objective To study the antifibrotic potency of sGC stimulators.Methods The effect of the sGC stimulator BAY 41-2272 on the release of collagen from dermal fibroblasts was examined. The antifibrotic effects of BAY 41-2272 on prevention and regression of fibrosis in bleomycin-induced dermal fibrosis and in Tsk-1 mice were also studied. Telemetric blood pressure studies in conscious mice were used to study potential hypotensive effects of sGC stimulation.Results sGC stimulation with BAY 41-2272 dose-dependently inhibited collagen release in dermal fibroblasts from patients with SSc and healthy individuals. Furthermore, BAY 41-2272 stopped the development of bleomycin-induced dermal fibrosis and skin fibrosis in Tsk-1 mice, preventing dermal and hypodermal thickening, reducing the numbers of myofibroblasts and reducing the hydroxyproline content. In addition, BAY 41-2272 was highly effective in the treatment of established fibrosis in the modified models of bleomycin-induced skin fibrosis and Tsk-1 mice. Treatment with sGC stimulators was well tolerated. Relevant antifibrotic doses of BAY 41-2272 did not affect systemic blood pressure and heart rate in mice.Conclusions These findings demonstrate potent antifibrotic effects and good tolerability of sGC stimulators in various experimental models of SSc. Given their potential vasoactive properties, sGC stimulators may be promising candidates for the dual treatment of fibrosis and vascular disease in SSc.