Delayed Progression of Edema Formation Around a Hematoma Expressing High Levels of VEGF and MMP-9 in a Patient With Traumatic Brain Injury: Case Report

Abstract

The mechanisms accounting for the development of tissue damage following traumatic brain injury (TBI) have been studied for several decades. A variety of mediators, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9), which play a crucial role in edema formation after TBI, have been identified. We experienced a case of brain edema that progressed continuously at least until 13 days after head injury. The brain edema occurred around the hemorrhage from an intracerebral contusion. The evacuated hematoma was investigated based on the inference that the unexpected expansion of edema was induced by the mediators within the hematoma itself. A 64-year-old woman was admitted to our hospital following a traffic injury. Left brain contusion was revealed by head computed tomography (CT) on admission. Three hours later, formation of an intracerebral hematoma became evident. Serial CT examination revealed that brain edema had developed progressively till 13 days after the injury. A hematoma removal operation was performed on Day 13. The hematoma was centrifuged and the supernatant was analyzed for the expression of VEGF and MMP-9. The values of both (4400 pg/ml and 920 ng/ml, respectively) were extremely high compared with values reported previously in serum and cerebrospinal fluid collected from patients with intracranial infection or injury. This case suggested that the delayed exacerbation of edema following traumatic intracranial hemorrhage was possibly induced by secretory factors such as VEGF and MMP-9 released from within and around the hematoma.

Pathogenesis of Brain Edema and Investigation into Anti-Edema Drugs

“…In central nervous tissue, the production of VEGFs is observed in astrocytes, neurons and endothelial cells [ 95 , 96 , 97 , 98 , 99 , 100 ]. An increase in VEGFs is seen in patients after brain insult [ 101 , 102 , 103 ]. Similar findings were also indicated in cold injury [ 1 ], FPI [ 104 , 105 ] and SAH experimental animal models [ 106 ].…”

“…Although MMPs support the repair of damaged nerve tissues by promoting angiogenesis as VEGFs do [ 119 ], their excessive action disrupts the integrity of vascular endothelial cells by degrading the basal lamina around brain microvessels, resulting in BBB hyperpermeability [ 120 ]. In patients with brain injury, up-regulation of MMPs has been indicated along with the severity of brain injury [ 102 , 121 , 122 , 123 ]. In central nervous tissue, the production of MMPs, especially MMP9, was observed in astrocytes, microglia, neurons and endothelial cells, and the increased MMP expression and activity were confirmed in experimental animals after brain insult [ 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 ].…”

Protection of the Blood–Brain Barrier as a Therapeutic Strategy for Brain Damage

“…[30][31][32] Increased VEGF expressions were observed after brain damage in experimental animal models [33][34][35] and in patients with brain damage. 8,36,37) Argaw et al 27) focused on astrocytic VEGF-A as a key driver of BBB permeability and confirmed that the inactivation of astrocytic VEGF-A reduced BBB breakdown, lymphocyte infiltration and inflammatory damage in a mouse model of multiple sclerosis (MS). BBB disruption was induced by the VEGF-induced down-regulation of CLN-5 and OCLN expressions.…”

“…60) In patients with TBI or cerebral ischemia, the up-regulation of MMPs was related to the severity of brain damage. [7][8][9] Thus, the beneficial effects of MMP inhibition for BBB disruptioninduced brain edema, inflammatory damage, and hemorrhage should be investigated in clinical trials.…”

“…In patients with brain damage, increased BBB disruptionrelated factors were observed and correlated with the severity of brain damage. [7][8][9] In this review, current investigations for novel therapeutic drugs of BBB disruption are summarized.…”