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.
Cerebral hemorrhage is a devastating form of stroke with high mortality and most survivors having long-term disability. Currently, there are no therapies for intracerebral hemorrhage. Brain injury is related to the release of hemoglobin from the hemorrhage into surrounding brain and this proposal seeks to control that release and determine methods of limiting hemoglobin- induced injury.
|Jing, Chaohui; Zhang, Haining; Shishido, Hajime et al. (2018) Association of Brain CD163 Expression and Brain Injury/Hydrocephalus Development in a Rat Model of Subarachnoid Hemorrhage. Front Neurosci 12:313|