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 有大量证据表明，红细胞裂解后释放的血红蛋白是脑损伤的原因之一。 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）。考虑到目前临床上尚无有效方法，如何减少此类损伤很重要。 经证实的脑出血治疗方法。一种参与限制的机制 血红蛋白的全身毒性是CD163，一种血红蛋白清道夫受体，它参与 当与触珠蛋白结合时，细胞摄取血红蛋白。然而，在脑 出血，我们最近的结果，得到其他人的支持，表明一些血红蛋白是 在大脑中 CD163 和其他防御机制上调之前释放（早期 红细胞溶解）。此外，虽然小胶质细胞 CD163 可能有利于清除血红蛋白， CD163 在神经元中也上调，并参与诱导细胞死亡。本次活动的目的 因此，建议是： 1) 确定早期血红蛋白从 脑血肿发生并可减少。 2) 检查CD163是否具有治疗作用 脑出血的目标。 3）确定CD163的调节机制 小胶质细胞和神经元，以便有可能独立操纵这些水平。这些 实验将涉及大鼠、小鼠和脑出血的体内和体外模型。 猪已经在我们的实验室中建立。

项目成果

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

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

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

CD47阻断抗体会加速血肿清除，并在实验性脑室出血后减轻脑积水。

• 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

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

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