Mehta Heena, Mashiko Shunya, Goulet Philippe-Olivier, Desjardins Jade, Pérez Gemma, Koenig Martial, Senécal Jean-Luc, Sarfati Marika
Immunoregulation Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Laboratory for Research in Autoimmunity, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 106(4):35-39. Epub 2017 Feb 8.
Dysregulated coagulation cascade has been implicated in development of fibrosis in systemic sclerosis (SSc). Thrombin, a key mediator of the coagulation pathway, has both proinflammatory and procoagulant properties. Here, we evaluated the efficacy of oral dabigatran, a direct thrombin inhibitor, on topoisomerase I dendritic cells (TOPOIA DCs)-induced lung and skin fibrosis, an experimental model of SSc.
Mice were repeatedly immunized with TOPOIA DCs. Dabigatran was administered in food either during the onset of fibrotic (late treatment) or inflammatory (early treatment) phase.
Early administration of dabigatran caused an aggravation of pulmonary fibrosis associated with signs of severe perivascular inflammation while late treatment was not protective when compared to the untreated TOPOIA DCs group. Thrombin was increased in lungs of TOPOIA DCs immunized group and, paradoxically, further augmented by administration of dabigatran to immunized mice. As in lungs, early and not late drug administration exacerbated skin fibrosis. Moreover, early dabigatran treatment induced a profibrotic and inflammatory skin gene expression signature with upregulated expression of Col5a1, Timp1, Tweakr, Vwf, Il6, Il33, Il4 and Ifng.
Dabigatran aggravated lung and skin fibrosis in a TOPOIA DCs-induced model of SSc-like disease. Therefore, our results argue against the use of dabigatran to treat patients with SSc.
凝血级联失调与系统性硬化症（SSc）的纤维化发展有关。凝血酶是凝血途径的关键介质，具有促炎和促凝血特性。在此，我们评估了直接凝血酶抑制剂口服达比加群对拓扑异构酶I树突状细胞（TOPOIA DCs）诱导的肺和皮肤纤维化（一种SSc实验模型）的疗效。
用TOPOIA DCs反复免疫小鼠。在纤维化期（晚期治疗）或炎症期（早期治疗）开始时，将达比加群添加到食物中给药。
与未治疗的TOPOIA DCs组相比，早期给予达比加群会加重肺纤维化，并伴有严重的血管周围炎症迹象，而晚期治疗并无保护作用。在TOPOIA DCs免疫组的肺中，凝血酶水平升高，矛盾的是，给免疫小鼠服用达比加群后，凝血酶水平进一步升高。与肺中情况相同，早期而非晚期给药会加重皮肤纤维化。此外，早期达比加群治疗诱导了促纤维化和炎症性皮肤基因表达特征，Col5a1、Timp1、Tweakr、Vwf、Il6、Il33、Il4和Ifng的表达上调。
在TOPOIA DCs诱导的类似SSc疾病模型中，达比加群加重了肺和皮肤纤维化。因此，我们的结果不支持使用达比加群治疗SSc患者。
