Early hematoma lysis and hemoglobin toxicity in intracerebral hemorrhage

脑出血的早期血肿溶解和血红蛋白毒性

• 批准号: 10378017
• 负责人: Richard F Keep
• 金额: $ 47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378017
• 关键词: Address; Adverse effects; Agonist; Animals; Appearance; Brain; Brain Injuries; Cell Death; Cerebral hemisphere hemorrhage; Cerebrum; Clinical; Coagulation Process; Complement Activation; Complement Inactivators; Complement Membrane Attack Complex; Cytolysis; Data; Defense Mechanisms; Dexamethasone; Elements; Erythrocyte Ghost; Erythrocytes; Family suidae; Female; Ferritin; Glucocorticoid Receptor; Haptoglobins; Hematoma; Hemoglobin; Hemolysis; Hemorrhage; Heparin; Histologic; Hour; Human; In Vitro; Injury; Iron; Iron Chelating Agents; Laboratories; Magnetic Resonance Imaging; Methods; Microglia; Mus; Neurologic Deficit; Neurons; PPAR gamma; Proteins; Rattus; Regulation; Role; Source; Stroke; Survivors; Time; Toxic effect; Up-Regulation; aged; antagonist; base; complement system; disability; experimental study; in vitro Model; in vivo; intraventricular hemorrhage; macrophage; male; mortality; neurotoxic; prevent; protective effect; receptor; scavenger receptor; systemic toxicity; therapeutic target; uptake

ABSTRACT There is much evidence that the hemoglobin released after erythrocyte lysis is a cause of brain injury after cerebral hemorrhage. This may be related to hemoglobin or its degradation products (e.g. iron). How to reduce such injury is important considering there are no current clinically proven therapies for intracerebral hemorrhage. One mechanism that is involved in limiting hemoglobin toxicity systemically is CD163, a hemoglobin scavenger receptor, which is involved in the cellular uptake of hemoglobin when bound to haptoglobin. However, in cerebral hemorrhage, our recent results, supported by others, indicates that some hemoglobin is released before CD163 and other defense mechanisms are upregulated in brain (early erythrolysis). In addition, while microglial CD163 may be beneficial in scavenging hemoglobin, CD163 is also upregulated in neurons and is involved in inducing cell death. The aims of this proposal are, therefore: 1) Determine the mechanisms by which early hemoglobin release from cerebral hematomas occurs and can be reduced. 2) Examine whether CD163 is a therapeutic target in intracerebral hemorrhage. 3) Determine the mechanisms regulating CD163 in microglia and neurons in order to potentially manipulate those levels independently. These experiments will involve in vivo and in vitro models of intracerebral hemorrhage in rats, mice and pig already established in our laboratories.

抽象的 有很多证据表明，红细胞裂解后释放的血红蛋白是大脑的原因 脑出血后受伤。这可能与血红蛋白或其降解产物有关 （例如铁）。考虑到临床上没有电流，如何减少这种伤害很重要 经过验证的脑出血的疗法。涉及限制的一种机制 血红蛋白毒性在系统上是CD163，一种血红蛋白清除剂受体，涉及 在与触觉球蛋白结合时，血红蛋白的细胞摄取。但是，在脑中 出血，我们最近得到的结果，得到了其他结果，表明某些血红蛋白是 在CD163和其他防御机制之前发行的大脑（早期） 红斑解释）。另外，虽然小胶质细胞CD163可能有益于清除血红蛋白，但 CD163在神经元中也被上调，并参与诱导细胞死亡。这个目的 因此，提案是：1）确定早期血红蛋白从 发生脑血肿，可以减少。 2）检查CD163是否是治疗性的 脑出血中的靶标。 3）确定调节CD163的机制 小胶质细胞和神经元可能独立地操纵这些水平。这些 实验将涉及大鼠，小鼠和小鼠的体内和体外脑出血模型 猪已经在我们的实验室中建立。

项目成果

Response by Hua et al to Letter Regarding Article, "Enhancement of Hematoma Clearance With CD47 Blocking Antibody in Experimental Intracerebral Hemorrhage".

• DOI: 10.1161/strokeaha.119.026620
• 发表时间: 2019-07
• 期刊: Stroke
• 影响因子: 8.3
• 作者: Y. Hua;R. Keep;G. Xi

Novel Approach to Visualize Microglia Death and Proliferation After Intracerebral Hemorrhage in Mice.

• DOI: 10.1161/strokeaha.122.040302
• 发表时间: 2022-11
• 期刊: STROKE
• 影响因子: 8.3
• 作者: Ye, Fenghui;Yang, Jinting;Hua, Ya;Keep, Richard F.;Xi, Guohua
• 通讯作者: Xi, Guohua

CD47 blocking antibody accelerates hematoma clearance and alleviates hydrocephalus after experimental intraventricular hemorrhage.

• DOI: 10.1016/j.nbd.2021.105384
• 发表时间: 2021-07
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Ye F;Hua Y;Keep RF;Xi G;Garton HJL
• 通讯作者: Garton HJL

The Fate of Erythrocytes after Cerebral Hemorrhage.

• DOI: 10.1007/s12975-021-00980-8
• 发表时间: 2022-10
• 期刊: TRANSLATIONAL STROKE RESEARCH
• 影响因子: 6.9
• 作者: Xia, Fan;Keep, Richard F.;Ye, Fenghui;Holste, Katherine G.;Wan, Shu;Xi, Guohua;Hua, Ya
• 通讯作者: Hua, Ya

Mechanisms of neuroinflammation in hydrocephalus after intraventricular hemorrhage: a review.

• DOI: 10.1186/s12987-022-00324-0
• 发表时间: 2022-04-01
• 期刊: Fluids and barriers of the CNS
• 影响因子: 7.3
• 作者: Holste KG;Xia F;Ye F;Keep RF;Xi G
• 通讯作者: Xi G