Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, China; and.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.
Blood. 2018 Mar 15;131(11):1219-1233. doi: 10.1182/blood-2017-09-807248. Epub 2017 Dec 29.
The pathogenesis of corticosteroid-resistant immune thrombocytopenia (ITP), a clinically challenging condition in which patients exhibit either no response to corticosteroids or are corticosteroid-dependent, remains poorly understood. Murine studies suggest that bone marrow (BM) endothelial progenitor cells (EPCs) play a crucial role in regulating megakaryocytopoiesis. However, little is known regarding the number and function of BM EPCs or how to improve impaired BM EPCs in corticosteroid-resistant ITP patients. In the current case-control study, we evaluated whether the BM EPCs in corticosteroid-resistant ITP differed from those in corticosteroid-sensitive ITP. Moreover, whether atorvastatin could enhance the number and function of BM EPCs derived from corticosteroid-resistant ITP patients was investigated in vitro and in vivo. Reduced and dysfunctional BM EPCs, characterized by decreased capacities of migration and angiogenesis as well as higher levels of reactive oxygen species and apoptosis, were observed in corticosteroid-resistant ITP patients. In vitro treatment with atorvastatin quantitatively and functionally improved BM EPCs derived from corticosteroid-resistant ITP patients by downregulating the p38 MAPK pathway and upregulating the Akt pathway, and rescued the impaired BM EPCs to support megakaryocytopoiesis. Subsequently, a pilot cohort study showed that atorvastatin was safe and effective in corticosteroid-resistant ITP patients. Taken together, these results indicate that reduced and dysfunctional BM EPCs play a role in the pathogenesis of corticosteroid-resistant ITP, and the impaired BM EPCs could be improved by atorvastatin both in vitro and in vivo. Although requiring further validation, our data indicate that atorvastatin represents a promising therapeutic approach for repairing impaired BM EPCs in corticosteroid-resistant ITP patients.
皮质类固醇耐药性免疫性血小板减少症（ITP）的发病机制尚不清楚，在这种临床上具有挑战性的情况下，患者表现为对皮质类固醇无反应或依赖皮质类固醇。 鼠类研究表明，骨髓（BM）内皮祖细胞（EPC）在调节巨核细胞生成中起关键作用。 然而，关于 BM EPC 的数量和功能，以及如何改善皮质类固醇耐药性 ITP 患者受损的 BM EPC 知之甚少。 在目前的病例对照研究中，我们评估了皮质类固醇耐药性 ITP 中的 BM EPC 是否与皮质类固醇敏感性 ITP 中的 BM EPC 不同。 此外，还研究了阿托伐他汀是否可以在体外和体内增强来自皮质类固醇耐药性 ITP 患者的 BM EPC 的数量和功能。 在皮质类固醇耐药性 ITP 患者中观察到数量减少和功能障碍的 BM EPC，其特征是迁移和血管生成能力降低以及活性氧和细胞凋亡水平升高。 阿托伐他汀体外治疗可通过下调 p38 MAPK 途径和上调 Akt 途径定量和功能上改善来自皮质类固醇耐药性 ITP 患者的 BM EPC，并挽救受损的 BM EPC 以支持巨核细胞生成。 随后的一项试点队列研究表明，阿托伐他汀在皮质类固醇耐药性 ITP 患者中是安全有效的。 总之，这些结果表明，数量减少和功能障碍的 BM EPC 在皮质类固醇耐药性 ITP 的发病机制中起作用，并且受损的 BM EPC 可以通过阿托伐他汀在体外和体内得到改善。 尽管需要进一步验证，但我们的数据表明，阿托伐他汀代表了一种有前途的治疗方法，可用于修复皮质类固醇耐药性 ITP 患者受损的 BM EPC。
