Mechanisms of Brain Injury after Intraventricular Hemorrhage

脑室内出血后脑损伤的机制

• 批准号: 8424950
• 负责人: GUOHUA XI
• 金额: $ 32.83万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8424950
• 关键词: Acute; Aneurysmal Subarachnoid Hemorrhages; Area; Autologous; Blood; Brain; Brain Edema; Brain Injuries; Canis familiaris; Cerebral hemisphere hemorrhage; Cerebrospinal Fluid; Cessation of life; Chelating Agents; Clinical; Complement; Cytolysis; Data; Deferoxamine; Dilatation - action; Erythrocytes; Ferritin; Goals; Heme; Hemoglobin; Hemorrhage; Hippocampus (Brain); Hour; Human; Hydrocephalus; Injection of therapeutic agent; Injury; International; Intracranial Hemorrhages; Intraventricular; Intraventricular Injections; Iron; Iron Chelation; Iron Overload; Ischemia; Liquid substance; Membrane; Modeling; Neurologic; Neurons; Operative Surgical Procedures; Outcome; Oxidative Stress; Oxygenases; Patients; Play; Prognostic Factor; Proteins; Rattus; Role; Subarachnoid Hemorrhage; Testing; Time; Tissues; Toxic effect; Up-Regulation; Ventricular; Whole Blood; aged; brain tissue; cerebral atrophy; complement system; heme oxygenase-1; intraventricular hemorrhage; mortality; neuron development

DESCRIPTION (provided by applicant): Intraventricular hemorrhage (IVH) occurs in many patients with intracerebral and subarachnoid hemorrhage (SAH). Recent studies have found IVH is a predictor of poor outcome after intracerebral hemorrhage and that hydrocephalus develops in 55% intracerebral hemorrhage patients with IVH. Hydrocephalus is also a major problem in SAH. Early hydrocephalus occurs in 20-50% SAH patients and is associated with poor clinical grade. However, the mechanisms of IVH-induced hydrocephalus are not well understood. Lysis of erythrocytes results in iron accumulation in the brain and causes brain damage after intracerebral hemorrhage. However, the role of erythrocyte lysis and iron toxicity in IVH-induced brain injury and hydrocephalus has still to be elucidated. Erythrocyte lysis after IVH may start very early. Hemoglobin released from red blood cells reaches its peak concentration by the second day following injection of blood into the cerebrospinal fluid of dogs. Hemoglobin release, from lysis of erythrocytes in human intracranial hemorrhage, increases during the first few days. Erythrocyte lysis appears to result from either depletion of intracellulr energy reserves or activation of the complement system. We have established an IVH model in rats and long-term ventricular dilatation has been observed. Recently we have found that hydrocephalus occurs in a model of SAH which results in intraventricular blood. Our preliminary data have demonstrated: 1) Intraventricular injection of autologous whole blood causes iron accumulation, hydrocephalus, neuronal death and brain tissue loss in the hippocampus; 2) Intraventricular injection of lysed erythrocytes rather than packed erythrocytes causes hydrocephalus by 24 hours; 3) Heme oxygenase-1 and ferritin levels are increased significantly in the hippocampus and periventricular areas following IVH; 4) Intraventricular injection of iron alone can also result in acute hydrocephalus; 5) Deferoxamine, an iron chelator, reduces IVH-induced hydrocephalus and hippocampal tissue loss. In this application, we propose to test the following specific aims: 1) Determine whether erythrocyte lysis and hemoglobin release cause hydrocephalus and neuronal death following IVH; 2) Determine whether complement inhibition reduces erythrocyte lysis and IVH/SAH-induced brain injury; 3) Examine the natural time courses of iron buildup, oxidative stress and upregulation of iron handling proteins in the brain after IVH; 4) Determine whether heme oxygenase inhibition reduces heme degradation and IVH/SAH-induced brain injury; and 5) Determine whether iron chelation reduces oxidative stress, hydrocephalus and neuronal death after IVH/SAH in aged rats. The purpose of our project is to investigate the mechanisms of brain injury after IVH. The long-term goal of our studies is to limit hemorrhagic brain damage in patients.

描述（由申请人提供）：脑室内出血（IVH）发生在许多脑内和蛛网膜下腔出血（SAH）患者中。最近的研究发现，IVH是脑出血后预后不良的一个预测指标，55%的IVH脑出血患者会发生脑积水。脑积水也是SAH的一个主要问题。早期脑积水发生在20-50%的SAH患者中，并与较差的临床分级相关。然而，ivh诱导脑积水的机制尚不清楚。红细胞溶解导致铁在脑内积聚，导致脑出血后脑损伤。然而，红细胞溶解和铁毒性在ivh诱导的脑损伤和脑积水中的作用仍有待阐明。体外受精后红细胞溶解可能很早就开始了。红细胞释放的血红蛋白在向犬脑脊液中注射血液后第二天达到峰值浓度。人颅内出血中红细胞溶解释放的血红蛋白在头几天增加。红细胞溶解似乎是由细胞内能量储备的消耗或补体系统的激活引起的。我们建立了大鼠IVH模型，观察到长期心室扩张。最近我们发现脑积水发生在SAH模型，导致脑室内血液。我们的初步数据表明：1)脑室内注射自体全血导致铁积聚、脑积水、神经元死亡和海马脑组织丢失；2)脑室内注射溶血红细胞而非充血红细胞可引起24小时脑积水；3) IVH后海马和心室周围血红素加氧酶-1和铁蛋白水平显著升高；4)单纯脑室内注射铁也可引起急性脑积水；铁螯合剂去铁胺可减少ivh诱导的脑积水和海马组织损失。在本应用中，我们拟测试以下具体目的：1)确定红细胞溶解和血红蛋白释放是否引起IVH后脑积水和神经元死亡；2)确定补体抑制是否减少红细胞溶解和IVH/ sah诱导的脑损伤；3)观察IVH后脑内铁积累、氧化应激和铁处理蛋白上调的自然时间过程；4)确定血红素加氧酶抑制是否减少血红素降解和IVH/ sah诱导的脑损伤；5)铁螯合是否能降低老年大鼠IVH/SAH后氧化应激、脑积水和神经元死亡。我们的项目目的是探讨IVH后脑损伤的机制。我们研究的长期目标是限制出血性脑损伤患者。