Traumatic Brain Injury (TBI) resulting from warfare could be violent, with severe brain damage, lacerations of blood vessels, and severe increases in intracranial pressure. Neurosurgeons for decades have recognized the need for control of pressure and mass balance within the skull. The most significant treatment has been the placement of a ventricular catheter which, by draining cerebrospinal fluid (CSF) and blood, modulates the content within the skull, controls pressure and washes out blood and debris from the brain. Despite manipulating the CSF outflow artificially for years, we have almost no information as to how the brain naturally drains CSF and scrubs itself of blood and debris. One reason is that only in large animals do arachnoid granulations exist, and many species, because of well developed lymphatics around their paranasal passages utilize other routes for material egress. The focus of this proposal therefore is to determine how the main outflow of CSF, the arachnoid, handles the dendritis from trauma using an ex vivo model developed in our laboratory. Especially significant are the massive quantities of extravasated blood as manifested by intracerebral, intraventricular, and subdural hemorrhages that need to be cleared not only to make room for the brain in the rigid skull, but also to remove the immense amount of oxidative products from heme that further damages the brain beyond the time period of the original insult. The arachnoid possesses the ability to form a barrier similar to the blood brain barrier (BBB) in the vascular endothelium/brain complex. The differences are several: 1) it is simpler, lacking the glial and neuronal invaginations that make u the neurovascular unit of the BBB, 2) its flow is mainly egressive, and 3) it has direct access to the CSF that circulates around, rinses, buffers, and protects the brain. Our hypothesis is that the arachnoid plays a key role in the removal of blood products from the brain due to TBI. To test this hypothesis, this proposal focuses on three specific aims: 1) understand the marked ability of these cells to tolerate the oxidative loads from blood, 2) determine how small blood products are transported by arachnoidal means, and 3) determine how micrometer-size debris is cleared by the arachnoid.
These aims would be studied by dividing transport into the paracellular and intracellular routes. By leveraging what we already know about barriers in the brain and what we will learn from this proposal, we can utilize treatments already developed and come up with immediate and novel treatments in the clearance of trauma products from the brain.
The brain is a soft gelatinous organ suspended in cerebrospinal fluid within the rigid cranial cavity. Blood vessels are poorly supported, with some of the major branches lying free in the subarachnoid space. With trauma, motion from blunt injury and lacerations from sharp injury may cause hemorrhages within the intracranial cavity. The brain is unique in that two major barriers separate it from the circulatory system. The blood brain barrier and the blood CSF barrier isolate the brain. Clinicians have long bypassed these barriers to rid the brain of debris and blood with surgery or with diversionary measures such as plastic tubing inserted into the ventricles. How the brain naturally removes the sometimes massive amount of blood is unknown, but studies have shown that over 70% may be trapped within the arachnoid and processed. The goal of this proposal therefore is to discover how the body clears blood and trauma from the brain and how to leverage these mechanisms to improve healing and speed recovery.