Matrix Metalloproteinase (MMP)-8 and MMP-9 in Cerebrospinal Fluid during Bacterial Meningitis: Association with Blood-Brain Barrier Damage and Neurological Sequelae

Abstract

To evaluate the spectrum and regulation of matrix metalloproteinases (MMPs) in bacterial meningitis (BM), concentrations of MMP-2, MMP-3, MMP-8, and MMP-9 and endogenous inhibitors of metalloproteinases (TIMP-1 and TIMP-2) were measured in the cerebrospinal fluid (CSF) of 27 children with BM. MMP-8 and MMP-9 were detected in 91% and 97%, respectively, of CSF specimens from patients but were not detected in control patients. CSF levels of MMP-9 were higher (P<.05) in 5 patients who developed hearing impairment or secondary epilepsy than in those who recovered without neurological deficits. Levels of MMP-9 correlated with concentrations of TIMP-1 (P<.001) and tumor necrosis factor-alpha (P=.03). Repeated lumbar punctures showed that levels of MMP-8 and MMP-9 were regulated independently and did not correlate with the CSF cell count. Therefore, MMPs may derive not only from granulocytes infiltrating the CSF space but also from parenchymal cells of the meninges and brain. High concentrations of MMP-9 are a risk factor for the development of postmeningitidal neurological sequelae.

Modular Transcriptional Activity Characterizes the Initiation and Progression of Autoimmune Encephalomyelitis

“…Our data is consistent with a previous report describing significant delay and in some cases total prevention of clinical EAE by Ab-mediated depletion of peripheral blood polymorphonuclear cells (20). The presence of Timp2 and Hp among this group of genes strengthens this hypothesis because matrix metalloproteinases and their inhibitors are known to play an early role in BBB damage (21)(22)(23). Also, Hp polymers have been previously identified as a sensitive indicator of BBB permeability (24,25).…”

Differential Effect of p47phoxand gp91phoxDeficiency on the Course of Pneumococcal Meningitis

“…In our model, cortical MMP-9 levels correlated significantly with accumulation of albumin in the cortex, a marker for BBB disruption. A correlation between the level of MMP-9 in CSF and BBB disruption has also been observed for patients suffering from bacterial meningitis (18). In a rat model of meningococcal meningitis, treatment with batimastat, which inhibits MMP-9 and other MMPs, effectively diminished BBB disruption and the increase in intracranial pressure (21).…”

Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

“…Pro-inflammatory cytokines/chemokines and interacts with the cytokines 48 . Gelatinases (MMP-2 and MMP-9) have shown to induce BBB breakdown and facilitate leukocyte extravasation in experimental bacterial meningitis 49 , furthermore, patients with bacterial meningitis present high concentrations of MMP-939 and MMP-8 in the CSF, indeed, high concentrations of MMP-9 were correlated with risk factor for the development of postmeningitis neurological sequelae 48 .…”

“…Gelatinases (MMP-2 and MMP-9) have shown to induce BBB breakdown and facilitate leukocyte extravasation in experimental bacterial meningitis 49 , furthermore, patients with bacterial meningitis present high concentrations of MMP-939 and MMP-8 in the CSF, indeed, high concentrations of MMP-9 were correlated with risk factor for the development of postmeningitis neurological sequelae 48 . In a rat model, adjuvant treatment with dexamethasone resulted in a lower MMP-9 mRNA 50 , in addition, combining the MMP and TNF-α inhibitors led to a decrease incidence of the seizures and mortality, furthermore, neuronal necrosis in the cortex and apoptosis in the hippocampus were attenuated in rats submitted by pneumococcal meningitis 51 .…”