Changes in MMP-9 and TIMP-1 Concentrations in Cerebrospinal Fluid after 1 Week of Treatment of Childhood Bacterial Meningitis

Abstract

We explored the changes of the initially highly upgraded cerebrospinal fluid matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of MMP 1 (TIMP-1) response during recovery of childhood bacterial meningitis and their association with outcome. The sizes of these changes varied substantially, but a steeper decrease in the MMP-9 and an increase of the TIMP-1 concentrations augured a better outcome. Matrix metalloproteinases (MMPs) are a group of zinc-dependent enzymes which, through their ability to degrade extracellular matrix and nonmatrix bioactive substances, can direct and modify multiple diverse biological and pathological processes, among them the inflammatory and immune responses (1). The MMP activities are inhibited by their specific endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs). Under physiological conditions, MMP activity is precisely regulated, whereas in disease, MMP activity is unbalanced (1).In childhood bacterial meningitis (BM), the initial concentrations of MMP-9 and TIMP-1 in the cerebrospinal fluid (CSF), and their molar ratio (MR), are highly upgraded, and the highest values are associated with adverse outcomes (2-6). We studied how the response was shut down and whether this process influenced the outcome. A better understanding of the response kinetics may open novel opportunities for therapeutic interventions (1, 7).The changes in the concentrations of MMP-9 and TIMP-1 and their MR from admission to 1 week of treatment (day 7) were analyzed using paired CSF samples taken, whenever enough CSF was available, on those days from patients of a previous BM study (8) ( Table 1; see also Fig. S1 in the supplemental material). All patients were treated with intravenous cefotaxime but were randomized to receive it during the first 24 h either as a continuous infusion or as an every-6-hour bolus (8). No adjuvant dexamethasone was given, but all the patients received oral glycerol (9). The audiological outcome was tested on day 7 by brain stem auditory evoked potentials (Madsen Octavus). Deafness was defined as a hearing threshold Ͼ80 dB in the better ear. Severe neurological sequelae were defined as blindness, quadriplegia or paresis, hydrocephalus requiring a shunt, or severe psychomotor retardation at discharge.The MMP-9 and TIMP-1 concentrations were determined by enzyme-linked immunosorbent assay (ELISA), as described previously (4). The changes in percent were compared with other data using the Spearman correlation for quantitative variables and the Mann-Whitney U test or Kruskal-Wallis test for nominal variables. The day-7 values also were examined in the same manner (see Tables S2 and S4 in the supplemental material). A P value of Ͻ0.05 was taken as significant.Within 1 week, the MMP-9 concentration fell by 90% (interquartile range [IQR], 28%) ( Fig. 1) from 476 ng/ml (IQR, 752 ng/ml) to 38 ng/ml (IQR, 62 ng/ml) (P Ͻ 0.0001). The children who later died (n ϭ 3) (Table 1) had a smaller decrease of 26% (IQR, 10%; P ϭ 0.02), and their day-7 MMP-9 concentration (see Table S2 in th...

Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis

“…MMP-9 inhibition by specific blocking antibodies partially abrogated BBB disruption. Our data is consistent with studies in multiple sclerosis, Alzheimer’s disease and bacterial meningitis where MMP-9 drove BBB dysfunction and neuronal injury 22 , 25 , 33 , 34 . VEGF expression has also been implicated in BBB disruption 35 , and a study in paediatric TB meningitis reported that VEGF levels correlated with CSF-serum albumin ratios and mononuclear cell counts 36 .…”

“…Increased MMP-9 was also detected in brain biopsies of patients with CNS TB 19 , and elevated MMP-9 concentrations in the CSF were associated with tissue injury and death 20 . Similarly, expression of the collagenase MMP-1 and stromelysin MMP-3 were increased in brain biopsies of patients with CNS TB 21 and were independent predictors of death 22 . To target MMP dysregulation, host directed therapy with MMP inhibitors has been investigated in CNS inflammatory conditions such as multiple sclerosis 23 .…”

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…is reduced compared to the acute phase of infection [144]. In pediatric PM, MMP-9 levels were found to correlate with CSF cell counts, with high CSF MMP-9 levels being a risk factor for fatal outcome or development of neurologic sequelae [35,141,144]. The causative pathogen determines the inflammatory response in patients with bacterial meningitis.…”

Predicting Outcome of Childhood Bacterial Meningitis With a Single Measurement of C-Reactive Protein

“…In both places, higher CRP correlated with a lower cerebrospinal fluid glucose concentration (ρ, −0.13; P = 0.04 and ρ, −0.19; P = 0.0003 in LatAm and Luanda, respectively). In Angola, increased CRP also associated with the Glasgow Outcome Score (ρ, −0.11; P = 0.04), initial cerebrospinal fluid matrix metalloproteinase-9 concentration 13 , 14 (ρ, 0.15; P = 0.03), and recovery with neurological sequelae ( P = 0.03).…”