Research ReportDexamethasone regulation of matrix metalloproteinase expression in experimental pneumococcal meningitis
Introduction
Bacterial meningitis is the most common serious infection of the central nervous system. Once bacteria have gained access to the central nervous system, the presence of multiplying bacteria within the subarachnoid and ventricular space compartments triggers an intense inflammatory host response aimed at killing the invading microorganisms. Proinflammatory mediators released in the process include tumour necrosis factor alpha (TNF-α) and matrix metalloproteinases MMPs (Leib et al., 2001).There is much evidence that MMPs contribute to the development of brain injury in bacterial meningitis (Leppert et al., 2000, Meli et al., 2004, Paul et al., 1998). MMPs facilitate leukocyte extravasation and brain edema by degradation of extracellular matrix components. Furthermore, MMPs sustain the inflammatory host responses by activating cytokines and cleaving cytokine receptors (Clements et al., 1997, Leib et al., 2000). In bacterial meningitis, MMP-9 are specifically up-regulated and act as effectors of subarachnoid space inflammation, brain edema, blood-brain barrier opening and neuronal injury (Leppert et al., 2000, Paul et al., 1998, Leib et al., 2000, Rosenberg et al., 1995).
Bacterial meningitis continues to result in significant brain injury in many patients, despite the use of highly active antibiotics (Durand et al., 1993). The prognosis of the disease is particularly poor in neonates suffering from bacterial meningitis (Franco et al., 1992). The mortality 5–30% and permanent neurologic deficits (30%) still highly occur following bacterial meningitis in children (Grimwood et al., 1996). Long-term neurological sequelae result from neuronal destruction due to an intense inflammatory response rather than from the infectious agent per se (Meli et al., 2006, McCracken and Saez-Llorens, 1997, Tunkel and Scheld, 1993). Accordingly, the glucocorticoid dexamethasone is used to protect the brain from the harmful effects of inflammation (Meli et al., 2006, McIntyre et al., 1997). Dexamethasone as adjunctive therapy to antibiotics has been shown to have beneficial effects on pathophysiological changes and neurological outcome in children with meningitis and in animal models. However, the role of dexamethasone in the pathophysiology of pneumococcal meningitis is still unknown. The effects of antibiotics on MMPs in bacterial meningitis have not been evaluated so far. We therefore intend to investigate the induction and expression of MMPs with special emphasis on the regulation of MMPs by dexamethasone and antibiotics in therapy of pneumococcal meningitis.
Here studies in a rat model of experimental Streptococcus pneumoniae meningitis were performed to investigate the kinetics of MMPs induced at the mRNA level in brain tissue. At the protein level, the activity of MMPs during disease development was delineated in the CSF. Meanwhile, this study evaluated the effect of dexamethasone and antibiotics of different dosage on MMPs in pneumococcal meningitis.
Section snippets
Histopathology of meningitis
By 24 h after infection, all infected rats fully developed meningitis. Bacterial culture of the homogenized cerebrospinal fluid of infected rats was positive for the same strain of S. pneumoniae but was negative before inoculation and in the rats injected with sterile saline as well as control groups. Histopathologically, the disease 24 h after infection was characterized by subarachnoid and ventricular inflammation, vasculopathy, and neuronal injury in cerebral cortex and hippocampus, while
Discussion
The major findings of the present study can be summarized as follows: first, MMP-9 mRNA and activity levels were increased in the brain after inoculation for 24 h with S. pneumoniae, while MMP-2 mRNA and activity remained at basal levels. Second, after antibiotic treatment of bacterial meningitis, MMP-9 mRNA and activity levels were very high, and there was a dose-dependent up-regulation of mRNA and activity levels by the antibiotic, but there was no change in MMP-9 mRNA and activity levels in
Infecting organism
The strain of serotype 3 S. pneumoniae, one of the most common types causing neonatal meningitis, was used (provided by the National Institute for the Control of Pharmaceutical and Biological Products, Beijing, China).The organism was grown on sheep blood agar plates, cultured overnight in VITAL AER broth and incubated overnight at 37 °C in air with 5% CO2 for the growing logarithmic phase. The culture broth was centrifuged, pelleted, resuspended in sterile saline to the desired density
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