title: Systemic inflammation alters the inflammatory response in experimental lipopolysaccharide-induced meningitis.
abstract: Experiments to evaluate the effect of the level and duration of endotoxaemia on the meningeal inflammatory response were performed in order to determine if systemic inflammation alters meningitis. Rabbits received either saline or Escherichia coli O111:B4 lipopolysacharide (LPS) intravenously at various doses (1, 3 or 10 microg) and times (-8, -2 or 0 h) before an intracisternal injection of 20 ng LPS. An intracisternal LPS injection together with saline intravenously produced a peak cerebrospinal fluid (CSF) tumour necrosis factor (TNF) level (95 +/- 26 ng/ml) at 2 h and peak leucocyte level (5413 +/- 764 cells/microl) at 4 h post-injection. Blood leucocytes were slightly elevated (12 000 +/- 500/microl at 0 h; 16 900 +/- 280/microl at 8 h) but plasma TNF was always undetectable (< 0.05 ng/ml). Conversely, intravenous injection of 3 or 10 microg LPS 2 h prior to intracisternal LPS injection impaired pleocytosis (peak < 220 cells/microl) and delayed ( approximately 4 h) and reduced peak CSF TNF levels (3 microg LPS 5.0 +/- 1.2 ng/ml; 10 microg LPS 6.9 +/- 1.9; P < 0.05). Intravenous administration of 1 microg LPS was less inhibitory to CSF inflammation, but delayed onset (peak 1100 +/- 60 leucocytes/microl CSF at 8 h; 6.3 +/- 0.3 ng TNF/ml CSF at 4 h; both P < 0.05). Neutropenia nadirs were dependent on LPS dose (1 microg, 4500 +/- 1700; 3 microg, 1900 +/- 60; 10 microg, 1100 +/- 100 all at 4 h post-intravenous dose). Peak plasma TNF levels were not dose-dependent (> 8 ng/ml), but plasma TNF was always detectable (> 0.2 ng/ml at 10 h post-intravenous dose). Intravenous LPS administration at 0 h also blocked pleocytosis, but the inhibitory effect was lost when administration at -8 h. In conclusion, the degree and duration of endotoxaemia affect the meningeal inflammatory response to LPS in experimental meningitis.
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel Switzerland. terence.oreilly@novartis.com
authors.forename: T
authors.initials: T
authors.lastname: O'Reilly
authors.forename: C
authors.initials: C
authors.lastname: Ostergaard
authors.forename: J
authors.initials: J
authors.lastname: Vaxelaire
authors.forename: O
authors.initials: O
authors.lastname: Zak
mesh_terms: D000818:Animals; D002555:Cerebrospinal Fluid / Q000382:microbiology; D004306:Dose-Response Relationship, Immunologic; D019446:Endotoxemia / Q000276:immunology*; D004926:Escherichia coli; D007267:Injections / Q000379:methods; D007275:Injections, Intravenous; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016920:Meningitis, Bacterial / Q000276:immunology*; D023421:Models, Animal; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid
chemical_list: D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha