title: Breakdown of the blood-brain barrier after fluid percussion brain injury in the rat: Part 2: Effect of hypoxia on permeability to plasma proteins.
abstract: Clinical studies have demonstrated that hypoxia after severe brain injury is common and significantly worsens neurologic outcome. We have, therefore, developed a rat model of posttraumatic hypoxic injury in order to identify the pathophysiologic responses after head injury that are worsened by this secondary insult. We examined the effect of hypoxia after brain injury on permeability of the blood-brain barrier to plasma proteins. Animals were divided into two experimental groups: group I (impact alone) and group IH (impact plus hypoxia). Rats were subjected to a lateral fluid percussive brain injury (4.8-5.2 atm). Animals in group IH were exposed to hypoxic conditions (10% O2) for 45 min immediately after injury. In each group, vascular permeability to endogenous immunoglobulins (IgG) and to horseradish peroxidase (HRP) was examined at the light microscopic level. IgG was immunolocalized in brain sections at 1-24 h after injury. In other studies, HRP was given i.v. either before impact or 10 min before killing. Permeability to this protein was assessed at 1-72 h after injury. The distribution of extravasated proteins was similar between the experimental groups at 1 h postinjury. Pronounced abnormal permeability to IgG and HRP (given before impact) occurred in discrete regions throughout both the ipsilateral and contralateral hemispheres. By 6 h after injury, a differential response of the blood-brain barrier was noted between groups I and IH. Widespread leakage of proteins was observed in the injured hemisphere in group IH. This finding was in sharp contrast to group I, in which extravasated proteins remained more localized in the injured hemisphere. The time course for reestablishment of the blood-brain barrier to HRP (given before killing) was determined. The impact site remained permeable to HRP up to at least 72 h postinjury within groups I and IH. In group I, the blood-brain barrier was reestablished in the parasagittal cortex and deep cortical layer by 6 h postinjury. In contrast, the blood-brain barrier in group IH was not restored in similar brain regions until 24 h postinjury. These studies demonstrate that (1) hypoxia after brain injury exacerbates the regional breakdown of the blood-brain barrier to circulating proteins, (2) this influence of hypoxia on permeability is not apparent immediately after injury but rather is expressed at 6 h after injury, and (3) hypoxia after traumatic brain injury delays recovery of the blood-brain barrier. These findings suggest that secondary posttraumatic hypoxia contributes to the vascular pathogenesis of brain injury.
authors.affiliation: Department of Neurosurgery, University of California, San Francisco.
authors.forename: H
authors.initials: H
authors.lastname: Tanno
authors.forename: R P
authors.initials: RP
authors.lastname: Nockels
authors.forename: L H
authors.initials: LH
authors.lastname: Pitts
authors.forename: L J
authors.initials: LJ
authors.lastname: Noble
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000502:physiology*; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D006651:Histocytochemistry; D006735:Horseradish Peroxidase; D002534:Hypoxia, Brain / Q000473:pathology / Q000503:physiopathology*; D007074:Immunoglobulin G / Q000378:metabolism; D008297:Male; D010474:Percussion; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001798:Blood Proteins; D007074:Immunoglobulin G; D006735:Horseradish Peroxidase