Mechanisms of Vaso-occlusion in Sickle Cell Disease

描述（由申请人提供）：镰状细胞病（SCO）发病率和死亡率的主要原因是由于血管闭塞导致的组织缺血和梗死，导致进行性器官损伤。尚不清楚SCO中观察到的促凝血或炎症活性增强是否直接导致镰状细胞血管闭塞性疾病的发病机制，或仅反映镰状红细胞引起的血管损伤。我们假设镰状红细胞最初损伤内皮，诱导促炎和促凝血表型;我们提出，炎症增加有助于可逆的血管淤滞，而凝血途径有助于完全停止血流和组织梗死。炎症和止血途径之间的密切相互关系建立了一个恶性循环，进一步传播了这一过程。因此，本项目的具体目的是：1）表征凝血酶生成和纤维蛋白形成对HbS诱导的内皮损伤、炎症和血管充血周期的影响，2）确定组织因子途径在镰状细胞诱导的血管病理学演变中的作用，3）研究蛋白C/血栓调节蛋白通路在HbS诱导的器官病理演变中的作用。我们将使用造血干细胞移植将SCO诱导到具有凝血和凝血信号通路的特定组分的遗传改变的小鼠中，并测试对炎症和内皮损伤的测量的影响。我们还将研究药物和遗传抗凝治疗在SCO小鼠以及缺氧-复氧治疗的SCO小鼠中的作用。最后，我们将在体内研究血栓形成和炎症对镰状红细胞粘附的作用。我们预期这些研究将阐明凝血系统、血管损伤和炎症在镰状细胞诱导的血管病理演变中的相互作用。此外，这些研究还将深入了解靶向抗凝/抗炎治疗对治疗和预防SCD血管病变的价值。

DESCRIPTION (provided by applicant): The major cause of morbidity and mortality in sickle cell disease (SCO) is tissue ischemia and infarction due to vascular occlusion that results in progressive organ damage. It is unclear whether the enhanced procoagulant or inflammatory activity observed in SCO directly contributes to the pathogenesis of sickle cell vaso-occlusive disease or merely reflects vascular injury caused by the sickle erythrocyte. We hypothesize that sickle erythrocytes initially injure the endothelium, inducing both a proinflammatory and procoagulant phenotype; we propose that the increased inflammation contributes to reversible vascular stasis while the coagulant pathway contributes to the complete stoppage of blood flow and tissue infarction. The strong interrelationships between the inflammatory and hemostatic pathways set up a vicious cycle that further propagates this process. Therefore, the Specific Aims for this project are to 1) Characterize the effects of thrombin generation and fibrin formation on the cycle of HbS-induced endothelial injury, inflammation and vascular congestion, 2) Define the role of the tissue factor pathway in the evolution of sickle cell-induced vascular pathology, and 3) Study the effect of modulation of the protein C/thrombomodulin pathway on the evolution of HbS-induced organ pathology. We will induce SCO into mice with genetic alterations of specific components of the coagulation and coagulant signaling pathways using hematopoietic stem cell transplantation and test the effect on measures of inflammation and endothelial injury. We will also examine the effect of pharmacologic and genetic anticoagulant therapy in SCO mice as well as hypoxia-reoxygenation-treated SCO mice. Finally, we will study the role of thrombosis and inflammation on sickle red cell adhesion in vivo. We anticipate that these studies will clarify the interrelated roles of the coagulation system, vascular injury and inflammation in the evolution of sickle cell-induced vascular pathology. Additionally, these studies will provide insights into the value of targeted anticoagulant/anti-inflammatory therapies for the treatment and prevention of SCD vascular pathology.