Biomedical subjects

Uwe Koedel

Publications and source records attributed to Uwe Koedel.

25 records · Page 2Linked to original sources

PubMed2003

Using knockout mice to study experimental meningitis.

Despite the use of antibiotics, the prognosis of bacterial meningitis is still poor due to central nervous system (CNS) complications, such as brain edema formation, cerebrovascular alterations, and intracranial hemorrhage. Experimental studies with animal models have given new insights into its pathophysiology during the acute phase of the disease. In recent years, genetically engineered mice have become a powerful tool in investigating the role of particular genes by targeted deletion and have also been applied in bacterial meningitis research. By using knockout mice, new knowledge of the roles of the different cytokines, proteases, and oxidants involved in the inflammatory cascade has emerged. In the future, temporal and cell type-specific control of gene expression will provide even more information on the impact of a particular gene on meningitis-induced brain damage.

Animals↗

PubMed2002

Pathophysiology of bacterial meningitis: mechanism(s) of neuronal injury.

No bacterial disease has undergone a more dramatic change in epidemiology during the past decade than acute bacterial meningitis. This review describes the changing epidemiology and considers some important recent observations that contribute to our understanding of the pathogenesis and pathophysiology of meningitis. The major focus is on the mechanisms of neuronal injury and the pathophysiologic concepts responsible for death and neurologic sequelae. In recent years, experimental studies have amplified our understanding of the substantial body of evidence that now implicates cytokines and chemokines, proteolytic enzymes, and oxidants in the inflammatory cascade leading to tissue destruction in bacterial meningitis. The molecular mechanisms responsible for oxidant-induced neuronal injury in meningitis are explored in some depth. Genetic targeting and/or pharmacologic blockade of the implicated pathways may be a future strategy for therapeutic adjunctive measures to improve outcome and may hold substantial promise, in concert with antimicrobial agents, in humans with acute bacterial meningitis.

Adolescent↗

PubMed2002

Role of the urokinase plasminogen activator system in patients with bacterial meningitis.

BACKGROUND: The urokinase plasminogen activator system has the potency to promote leukocyte recruitment and blood-CSF barrier breakdown, and thus may play an important pathophysiologic role in bacterial meningitis. METHODS: CSF and serum concentrations of urokinase-plasminogen activator (urokinase [uPA]), uPA receptor (uPAR), and PA inhibitor-1 (PAI-1) were quantified by ELISA in 12 patients with bacterial meningitis, control patients (n = 10) with noninflammatory neurologic diseases, and 10 patients with Guillain-Barré syndrome (GBS), a disease in which blood-CSF barrier disruption occurs without CSF pleocytosis. Casein zymography was used to determine PA-dependent plasminogen activation in the CSF. RESULTS: A marked increase in uPA-dependent plasminogen activation was detected in the CSF of patients with bacterial meningitis vs CSF of patients with GBS and controls. Accordingly, ELISA analysis of CSF revealed intrathecal upregulation of uPA protein in patients with bacterial meningitis. CSF concentrations of uPAR and PAI-1 were also elevated in these patients. The serum of patients with bacterial meningitis showed elevated protein levels of uPA, but not uPAR or PAI-1. Positive correlations were found between blood-CSF barrier breakdown and CSF uPA concentrations, and between CSF pleocytosis and CSF/serum ratios of the potent chemokine uPAR in patients with bacterial meningitis. Furthermore, an adverse clinical outcome in these patients correlated with serum uPA concentrations. CONCLUSION: In bacterial meningitis, the urokinase plasminogen activator system is involved in leukocyte recruitment and breaching of the blood-CSF barrier, and this may contribute to an unfavorable clinical outcome.

Adult↗

PubMed2002

Role of Caspase-1 in experimental pneumococcal meningitis: Evidence from pharmacologic Caspase inhibition and Caspase-1-deficient mice.

Caspase 1 plays a pivotal role in generating mature cytokine interleukin-1beta. Interleukin-1beta is implicated as a mediator of pneumococcal meningitis, both in experimental models and in humans. We demonstrated here that (1) Caspase 1 mRNA and protein expression is upregulated in the brain during experimental pneumococcal meningitis, and (2) Caspase 1 levels are elevated in the cerebrospinal fluid of patients with acute bacterial meningitis. The upregulation/activation of Caspase 1 was associated with increased levels of interleukin-1beta. Depletion of the Caspase 1 gene and pharmacologic blockade of Caspase 1 significantly attenuated the meningitis-induced increase in interleukin-1beta. This was paralleled by a significantly diminished inflammatory host response to pneumococci. The antiinflammatory effect of Caspase 1 depletion or blockade was associated with a marked reduction of meningitis-induced intracranial complications, thus leading to an improved clinical status. In humans, cerebrospinal fluid Caspase 1 levels correlated with the clinical outcome. Thus, pharmacologic inhibition may provide an efficient adjuvant therapeutic strategy in this disease.

Amino Acid Chloromethyl Ketones↗

PubMed2002

Pathogenesis and pathophysiology of pneumococcal meningitis.

Until the introduction of antibiotics in the 1930s and 1940s, acute bacterial meningitis was fatal in most cases. Since then it has become curable with a variable mortality and morbidity rate for individual pathogens and patients. Neuropathological and clinical studies have shown that a fatal outcome of the disease is often due to central nervous system (CNS) complications including cerebrovascular involvement, brain oedema formation, and hydrocephalus resulting in increased intracranial pressure and seizure activity. During recent years, experimental studies with animal models have substantially increased our knowledge of the interactions of bacterial pathogens with mammalian cells and their entry into the CNS, and the complex pathophysiological mechanisms of brain dysfunction during acute bacterial meningitis. There is now a substantial body of evidence that cytokines, chemokines, proteolytic enzymes, and oxidants are involved in the inflammatory cascade that leads to tissue destruction in bacterial meningitis. Genetic targeting and/or pharmacological blockade of these pathways was beneficial in experimental bacterial meningitis. Apart from dexamethasone, these treatment strategies hold major promise for the adjunctive therapy of acute bacterial meningitis in clinical practice.

Animals↗

PubMed2002

Meningitis-associated central nervous system complications are mediated by the activation of poly(ADP-ribose) polymerase.

The present study assessed the role of PARP [poly(adenosine diphosphate-ribose) polymerase] activation in experimental pneumococcal meningitis. Mice with a targeted disruption of the PARP 1 gene were protected against meningitis-associated central nervous system complications including blood-brain barrier breaching and increase in intracranial pressure. This beneficial effect was paralleled by a significant reduction in meningeal inflammation, as evidenced by significantly lower cerebrospinal fluid leukocyte counts and interleukin-1beta, -6, and tumor necrosis factor-alpha concentrations in the brain (compared with infected wild-type mice). The reduction in inflammation and central nervous system complications was associated with an improved clinical status of infected, PARP 1-deficient mice. A similar protective effect was achieved by PARP inhibition using 3-aminobenzamide, the pharmacologic efficacy of which was confirmed by a marked attenuation of meningitis-induced poly(ADP)ribose formation. When the rat brain-derived endothelial cell line GP8.3 was cocultured with macrophages, exposure to pneumococci induced endothelial cell death and was paralleled by PARP activation and a reduction in the oxidized form of cellular nicotinamide adenine dinucleotide content. Treatment with 3-aminobenzamide significantly attenuated cellular nicotinamide adenine dinucleotide depletion and pneumococci-induced cytotoxicity. Thus, PARP activation seems to play a crucial role in the development of meningitis-associated central nervous system complications and pneumococci-induced endothelial injury. Inhibitors of PARP activation could provide a potential therapy of acute bacterial meningitis.

Animals↗

PubMed2002

Experimental bacterial meningitis in rats: demonstration of hydrocephalus and meningeal enhancement by magnetic resonance imaging.

We investigated whether magnetic resonance imaging (MRI) is able to detect intracranial manifestations of advanced bacterial meningitis in rats. Meningitis was induced in nine animals by injecting 150 microl 10(7) colony forming units per ml of Streptococcus pneumoniae into the cisterna magna. MRI was performed 24 h (n = 5) and 48 h (n = 4) after infection. Controls included (I) animals that were injected intracisternally with 150 microl phosphate-buffered saline or (II) animals without puncture of the cisterna magna. T2-weighted and T1-weighted MR images before and after administration of 0.3 mmol kg(-1) of gadolinium-DTPA were obtained. Hydrocephalus was found in 7 of 9 infected animals, but not in the control group. Abnormal leptomeningeal enhancement was found in all infected animals, but in none of the controls. The animals imaged after 48 h showed a more pronounced hydrocephalus and a more intense leptomeningeal enhancement than animals imaged after 24 h. Even in small animals such as rats, MRI can be used to detect the presence of bacterial meningitis and its associated complications. MRI may be a useful noninvasive method for monitoring the possible effect of adjunctive therapeutic strategies in experimental studies of meningitis.

Animals↗