Induction of Tissue Factor by Patient Sera in HUS

HUS 患者血清诱导组织因子

• 批准号: 7039868
• 负责人: Eric Franklin Grabowski
• 金额: $ 25.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039868
• 关键词: blood chemistry; blood coagulation; children; clinical research; cytokine; hemolytic anemia; human subject; human tissue; laboratory rabbit; patient oriented research; renal failure; serum; shiga toxin; thromboplastin; vascular endothelium

DESCRIPTION (provided by applicant): Diarrhea-positive Hemolytic Uremic Syndrome (D+ HUS) is a serious disease in children that causes hemolytic anemia, thrombocytopenia, and acute renal failure. In fact, it is the most common cause of acute renal failure in children. During the acute phase of the HUS, some 3 to 5% of patients die, while as many as 25% also suffer stroke, seizures, and/or coma. At present this condition has little established pathophysiology, aside from an association with shiga toxin produced by strains of Escherichia coli and the presence of plasma markers indicative of a prothrombotic state. We have previously demonstrated that shiga toxin significantly increases the expression of functional tissue factor (TF) by TNF-alpha-activated human glomerular endothelial cells (HGECs). Therefore, we hypothesize that increased TF activity plays an important role in the pathophysiology of HUS. Through this grant we aim 1) to demonstrate that kidney sections from a rabbit model of HUS are prothrombotic as compared to control kidney tissue; 2) to demonstrate that sera from patients with HUS augment the expression of TF, while the blood of these patients contains TF-positive circulating endothelial cells and microparticles; and 3) to use monolayers of HGECs, patient platelet adhesion/aggregation in flowing blood, and kidney from the rabbit model to test inhibitors of the TF pathway as potential therapies for HUS. These inhibitors include recombinant-TF pathway inhibitor, an antibody directed against activated factor X, recombinant-activated protein C, and active site-inhibited r-factor VIIa. A confirmation that shiga toxin and cytokines present in patient sera augment the TF pathway in our model system coupled with a demonstration that pharmacologic interruption of this pathway is both effective and feasible, will help to develop a novel, effective therapy for childhood HUS, where at present only supportive care is available. A key additional feature of this proposal is the use of our newly formed collaborative group of pediatric nephrologists to facilitate patient recruitment

描述(由申请人提供)： 腹泻阳性溶血性尿毒症综合征(D+HUS)是一种严重的儿童疾病，可导致溶血性贫血、血小板减少和急性肾功能衰竭。事实上，它是导致儿童急性肾功能衰竭的最常见原因。在HUS的急性期，约3%至5%的患者死亡，而多达25%的患者还遭受中风、癫痫发作和/或昏迷。目前，除了与大肠杆菌菌株产生的志贺毒素和指示血栓前状态的血浆标志物的存在有关外，这种情况几乎没有确定的病理生理学基础。我们先前已经证明志贺毒素显著增加肿瘤坏死因子-α激活的人肾小球内皮细胞(HGECs)功能组织因子(TF)的表达。因此，我们推测Tf活性升高在HUS的病理生理学中起重要作用。通过这笔赠款，我们的目的是：1)证明HUS兔模型的肾脏切片与对照肾组织相比是血栓形成的；2)证明HUS患者的血清增强了TF的表达，而这些患者的血液中含有TF阳性的循环内皮细胞和微粒；3)使用HGEC单层、患者流动血液中的血小板黏附/聚集以及兔模型的肾脏来测试TF途径的抑制剂作为HUS的潜在治疗方法。这些抑制物包括重组转铁蛋白途径抑制物、针对活化因子X的抗体、重组活化蛋白C和活性部位抑制的r-因子VIIa。证实患者血清中的志贺毒素和细胞因子增加了我们模型系统中的转铁蛋白途径，再加上药物阻断这一途径是有效和可行的，这将有助于开发一种新的、有效的治疗儿童HUS的方法，目前只有支持性护理可用。这项提议的另一个关键特点是利用我们新成立的儿科肾病医生协作小组来促进患者招募