Atorvastatin enhances bone marrow endothelial cell function in corticosteroid-resistant immune thrombocytopenia patients

作者：Kong, Yuan; Cao, Xie-Na; Zhang, Xiao-Hui; Shi, Min-Min; Lai, Yue-Yun; Wang, Yu; Xu, Lan-Ping; Chang, Ying-Jun; Huang, Xiao-Jun^*

来源：Blood, 2018, 131(11): 1219-1233.

DOI：10.1182/blood-2017-09-807248

• HIGH-DOSE DEXAMETHASONE
• PROLONGED ISOLATED THROMBOCYTOPENIA
• VITRO MEGAKARYOCYTE PRODUCTION
• HEMATOPOIETIC STEM-CELLS
• POOR GRAFT FUNCTION
• PROGENITOR CELLS
• PLATELET PRODUCTION
• ADULT PATIENTS
• T-CELLS
• PURPURA

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.

• 出版日期2018-3-15
• 单位北京大学