The Effect of Hemorrhagic Shock and Resuscitation on Blood‐Brain Barrier Integrity

Abstract

Hemorrhagic shock (HS) is a primary cause of death after trauma. In many non‐brain injured patients, neurobehavioral changes have been observed after injury and HS suggesting distant effects on the brain from extracranial trauma. We here explore the effects of HS and resuscitation on blood‐brain barrier (BBB) integrity. Male C57BL/6J mice were subjected to HS at a MAP of 35mmHg for 60 min. Mice were then resuscitated with shed blood and lactated ringers solution. Mice were sacrificed at time after HS, and 2, 24, and 72 hours after resuscitation (HS+R). Mouse brain sections were immunohistochemically assayed for expression of the tight junction proteins ZO‐1 and Claudin‐5. In separate experiments, Evan's blue (EB) dye was injected via tail vein 1 hr before sacrifice and brain sections were examined for evidence of BBB permeability. ZO‐1 was greatly reduced in the mouse brain in HS alone, HS+R 2 hr and HS+R 24hr mice, with a marked restoration of signal in HS+R 72hr mice. Claudin‐5 expression remained unchanged. EB extravasation was observed in the mouse brain following HS, with the most notable extravasation seen in the hippocampus of HS+R 2hr mice. These results suggest that BBB permeability is increased following HS and resuscitation, likely mediated by decreased ZO‐1. Future studies will investigate the dynamic quantitative changes of BBB permeability and its mechanisms. Support: DOD W81XWH‐10‐1‐0509, NIH 5GM085689.