Mechanisms of Brain Injury after Intraventricular Hemorrhage

脑室内出血后脑损伤的机制

• 批准号: 8995697
• 负责人: GUOHUA XI
• 金额: $ 34.02万
• 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995697
• 关键词: Acute; Aneurysmal Subarachnoid Hemorrhages; Area; Autologous; Blood; Brain; Brain Edema; Brain Injuries; Canis familiaris; Cerebral hemisphere hemorrhage; Cerebrospinal Fluid; Chelating Agents; Clinical; Complement; Cytolysis; Data; Deferoxamine; Development; 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; 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 loss

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。近年来的研究发现，脑出血后IVH是预后不良的一个预测因素，55%的脑出血伴IVH患者发生脑积水。脑积水也是SAH的主要问题。20-50%的SAH患者会出现早期脑积水，并且与临床分级较差相关。然而，IVH引起脑积水的机制还不清楚。 脑出血后红细胞溶解导致铁在脑中积聚并引起脑损伤。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。IVH后红细胞溶解可能很早就开始。从红细胞释放的血红蛋白在将血液注射到狗的脑脊髓液中后的第二天达到其峰值浓度。人颅内出血红细胞溶解释放的血红蛋白在最初几天内增加。红细胞溶解似乎是由于细胞内能量储备耗尽或补体系统激活引起的。 我们建立了大鼠IVH模型，并观察到长期的心室扩张。最近，我们发现脑积水发生在SAH模型中，导致脑室内血液。我们的初步资料表明：1）脑室注射自体全血可引起海马铁蓄积、脑积水、神经元死亡和脑组织丢失; 2）脑室注射裂解红细胞而不是浓缩红细胞可引起24小时脑积水; 3）IVH后海马和脑室周围区血红素氧合酶-1和铁蛋白水平显著升高; 4）单独脑室内注射铁也可导致急性脑积水; 5）去铁胺，一种铁螯合剂，减少IVH诱导的脑积水和海马组织损失。在本申请中，我们提出测试以下具体目的：1）确定IVH后红细胞溶解和血红蛋白释放是否引起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）检查IVH后脑中铁积累、氧化应激和铁处理蛋白上调的自然时程; 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;和5）确定铁螯合是否减少老龄大鼠中IVH/SAH后的氧化应激、脑积水和神经元死亡。 本课题旨在探讨IVH后脑损伤的机制。我们研究的长期目标是限制患者的出血性脑损伤。