BIOPHYSICS OF SICKLE CELL/ENDOTHELIAL CELL ADHERENCE

描述：研究人员建议继续研究 镰状细胞粘附于血管内皮细胞的机制 微血管，如其摘要进一步描述的： “血红蛋白SS在低氧张力下的聚合被认为是 镰状细胞病的主要因素。 由于形态学镰状化是 血红蛋白脱氧后延迟，减缓红细胞 微循环转运可能是微血管闭塞的先兆， 缺血性组织损伤和镰状细胞特征性疼痛发作 贫血 我们假设镰状红细胞粘附于微血管 内皮细胞延迟红细胞微循环转运启动或 传播血管阻塞。 我们的研究已经确定了血浆因子，红色 细胞受体和内皮细胞粘附分子， 流动下的细胞粘附。 在体内，粘附必须在 动态条件和附着力必须足够强以承受剪切 流动的血液使闭塞的血管和组织再灌注所施加的力。 因此，受体、细胞粘附分子和粘附蛋白是 必要的，但不足以镰状细胞粘附和血管闭塞。 我们假设，在体内，粘附生物物理学（主要是强度）将 调节镰状细胞粘附和血管闭塞的程度。 条件 这将导致广泛和强烈的遵守将是最相关的 镰状细胞粘附和体内血管闭塞的病理生理学。 到 为了解决这个问题，我们设计了以下实验， 目的：（1）证明流动下的镰状细胞粘附更强 在静态条件下的遵守和在流动条件下的遵守 对于表达更多粘附受体的细胞;（2）量化 镰状细胞/内皮细胞粘附响应于红细胞激动剂， 内皮激活剂和细胞群的粘附血浆蛋白 和单个细胞在0 - 10达因/cm 2剪切应力范围内。 特别强调的是， 模拟可能引起疼痛的临床状况的依从性途径 体内事件，如血栓形成或感染;（3）开发流动通道 具有小静脉尺寸（20-50微米），并证明镰状细胞 在受限通道中的粘附是强的。 “分析镰状细胞粘附于内皮细胞的生物物理学 模拟微循环的条件将提供 进入生理条件，促进广泛，快速，强大， 镰状细胞/内皮细胞粘附可能导致血管闭塞性疼痛 情节。 这些研究将确定最重要的参数， 粘附途径，以开发治疗剂， 抑制或逆转粘附以改善镰状细胞疼痛发作。"

DESCRIPTION: The investigators propose to continue studies on the mechanisms of sickle cell adhesion to endothelial cells of the microvasculature, as further described by their abstract: "Polymerization of hemoglobin SS at low oxygen tension is assumed to be the dominant factor in sickle cell pathology. Since morphologic sickling is delayed after hemoglobin deoxygenation, factors which slow red cell microcirculatory transit are likely antecedents to microvascular occlusion, ischemic tissue damage, and pain episodes characteristic of sickle cell anemia. We hypothesize that sickle erythrocyte adherence to microvascular endothelium delays erythrocyte microcirculatory transit to initiate or propagate vaso-occlusion. Our studies have identified plasma factors, red cell receptors, and endothelial cell adhesion molecules which promote sickle cell adherence under flow. In vivo, adherence will have to occur under dynamic conditions and adhesion must be strong enough to withstand shear forces exerted by flowing blood to reperfuse occluded vessels and tissues. Thus, receptors, cell adhesion molecules, and adhesive proteins are necessary, but not sufficient for sickle cell adherence and vaso-occlusion. We hypothesize that in vivo, adherence biophysics (primarily strength) will regulate the extent of sickle cell adhesion and vaso-occlusion. Conditions which lead to extensive and strong adherence will be most relevant to the pathophysiology of sickle cell adherence and vaso-occlusion in vivo. To address this, experiments have been designed with the following specific aims: (1) Demonstrate that sickle cell adherence under flow is stronger than adherence under static conditions and that adherence under flow selects for cells expressing more adhesion receptors; (2) Quantify the strength of sickle-cell/endothelial adherence in response to red cell agonists, endothelial activators, and adhesive plasma proteins for cell populations and individual cells in the range of 0 - 10 dynes/cm2 shear stress. Particular emphasis will be placed on conditions which invoke multiple adherence pathways to mimic clinical conditions which may precipitate pain episodes in vivo, such as thrombosis or infection; (3) Develop flow channels with venular dimensions (20-50 micrometers) and demonstrate that sickle cell adherence in confined channels is strong. "Analysis of the biophysics of sickle cell adherence to endothelium under conditions which mimic those in the microcirculation will provide insights into the physiological conditions which promote extensive, rapid, and strong sickle cell/endothelial cell adherence likely leading to vaso-occlusive pain episodes. These studies will identify the most important parameters and adherence pathways to target for the development of therapeutic agents to inhibit or reverse adherence to ameliorate sickle cell pain episodes."