Elevation of matrix metalloproteinases 3 and 9 in cerebrospinal fluid and blood in patients with severe traumatic brain injury.
OBJECTIVE
Traumatic brain injury (TBI) causes an increase in matrix metalloproteinases (MMPs), which are associated with neuroinflammation, blood-brain barrier disruption, hemorrhage, and cell death. We hypothesized that patients with TBI have an increase in MMPs in ventricular cerebrospinal fluid (CSF) and plasma.


METHODS
Patients with TBI and a ventricular catheter were entered into the study. Samples of CSF and plasma were collected at the time of catheter placement and at 24 and 72 hours after admission. Seven TBI patients were entered into the study, with 6 having complete data for analysis. Only patients who had a known time of insult that fell within a 6-hour window from initial insult to ventriculostomy were accepted into the study. Control CSF came from ventricular fluid in patients undergoing shunt placement for normal pressure hydrocephalus. Both MMP-2 and MMP-9 were measured with gelatin zymography and MMP-3 with Western immunoblot.


RESULTS
We found a significant elevation in the levels of the latent form of MMP-9 (92-kD) in the CSF obtained at the time of arrival (P < 0.05). Elevated levels of MMP-2 were detected in plasma at 72 hours, but not in the CSF. Using albumin from both CSF and blood, we calculated the MMP-9 index, which was significantly increased in the CSF, indicating endogenous MMP production. Western immunoblot showed elevated levels of MMP-3 in CSF at all times measured, whereas MMP-3 was not detected in the CSF of normal pressure hydrocephalus.


CONCLUSIONS
We show that MMPs are increased in the CSF of TBI patients. Although the number of patients was small, the results were robust and clearly demonstrated increases in MMP-3 and MMP-9 in ventricular CSF in TBI patients compared with controls. Although these preliminary results will need to be replicated, we propose that MMPs may be important in blood-brain barrier opening and hemorrhage secondary to brain injury in patients.
Grossetete
Mark
M
Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-0001, USA.
Phelps
Jeremy
J
Arko
Leopold
L
Yonas
Howard
H
Rosenberg
Gary A
GA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis / Q000097:blood / Q000134:cerebrospinal fluid; D001812:Blood-Brain Barrier / Q000201:enzymology / Q000503:physiopathology; D001921:Brain / Q000201:enzymology / Q000503:physiopathology; D001930:Brain Injuries / Q000097:blood / Q000134:cerebrospinal fluid / Q000201:enzymology; D005260:Female; D006801:Humans; D006850:Hydrocephalus, Normal Pressure / Q000209:etiology / Q000503:physiopathology / Q000601:surgery; D020300:Intracranial Hemorrhages / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D019586:Intracranial Hypertension / Q000209:etiology / Q000503:physiopathology; D019278:Matrix Metalloproteinase 3 / Q000032:analysis / Q000097:blood* / Q000134:cerebrospinal fluid*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000097:blood* / Q000134:cerebrospinal fluid*; D008875:Middle Aged; D015854:Up-Regulation / Q000502:physiology; D014696:Ventriculostomy; D055815:Young Adult
D015415:Biomarkers; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9