The cerebrospinal fluid inflammatory response

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Once the organism has invaded the cerebrospinal fluid, a number of bacterial components, particularly lipopolysaccharide or lipo-oligosaccharide of Gram-negative organisms and peptidoglycan are the major determinants of meningeal inflammation. The techoic acid of Gram-positive organisms and the peptidoglycan components of both Gram-positive and Gram-negative organisms have been shown to be potent inducers of inflammation in the cerebrospinal fluid and to impair blood-brain barrier function on direct intracisternal inoculation in experimental animals. Similarly, direct inoculation of lipopolysaccharide from H. influenzae or the lipo-oligosaccharide of N. meningitidis into the cerebrospinal fluid of experimental animals causes an intense inflammatory reaction with influx of leukocytes, increase in protein and lactate, and a decline in cerebrospinal fluid glucose concentration. These studies have provided overwhelming evidence that bacterial endotoxins and other bacterial cell wall constituents are important in the initiation of the inflammatory changes within the cerebrospinal fluid and disturbance of function of the blood-brain barrier (Quagliarell.o.a.Dd.Scheld 1992 )

The inflammatory changes in the cerebrospinal fluid occur several hours after inoculation of bacteria or cell wall constituents into the meningeal space of experimental animals. This has led to the hypothesis that elaboration and release of host mediators are instrumental in the development of the inflammatory changes. Animal models have established that tumor necrosis factor-a and interleukin 1b (IL-1b) are important mediators of the initial meningeal inflammation. Levels of tumor necrosis factor-a and IL-1b, together with interleukin 6 (IL-6), increase in the cerebrospinal fluid of animals following intracisternal inoculation of meningococcal lipo-oligosaccharide, and this rise in cytokine levels precedes cellular influx and protein exudation. These cytokine mediators have been shown to stimulate the release of other factors in the inflammatory cascade, including platelet activating factor, interleukin 8 (IL-8), and interferon-g. Release of these proinflammatory mediators causes upregulation of cellular adhesion molecules, which include molecules such as the integrins, selectins, and the IgG superfamily, on the surface of peripheral blood leukocytes and vascular endothelial cells of the blood-brain barrier. This results in attraction, attachment, and migration of leukocytes into the cerebrospinal fluid. Once present in the cerebrospinal fluid, polymorphonuclear neutrophils are activated and undergo degranulation and release of proteolytic enzymes, cationic proteins, and reactive oxygen species. These products further alter the integrity of the blood-brain barrier, thus interrupting its primary functions, i.e. active transport and facilitated diffusion of nutrients (including glucose and other metabolites) and secretion of cerebrospinal fluid. Increased permeability of the blood-brain barrier results in leakage of albumin and other macromolecules into the cerebrospinal fluid, causing vasogenic edema. The presence of the anaphylotoxins (C3a, C5a) in the cerebrospinal fluid due to the protein leak further encourages passage of polymorphonuclear neutrophils into the cerebrospinal fluid, thus accentuating the inflammatory process. Toxic products of neutrophil activation and other inflammatory cells cause cytotoxic edema and damage to surrounding cells.

Recently, nitric oxide (NO) has been implicated as a potential neurotoxic factor. NO is produced by a variety of cell types and is involved in processes such as smooth muscle relaxation, regulation of cell-mediated cytotoxicity, inhibition of platelet aggregation, and neuronal signaling. Cytokines, such as those described above, together with lipopolysaccharide induce the formation of large amounts of NO via the enzyme inducible NO synthase (iNOS) in microglia and astrocytes. This implies a possible role for NO in the host response to bacterial meningitis. A recent study has shown increased levels of cerebrospinal fluid nitrite and nitrate (degradation products of NO) in patients with bacterial meningitis, which correlated with the level of tumor necrosis factor-a in the cerebrospinal fluid.

The importance of the cytokines has been confirmed in studies where direct inoculation of tumor necrosis factor-a, IL-1b, and interferon-g into the cerebrospinal fluid of experimental animals induces inflammatory changes which closely resemble those which are seen with lipopolysaccharide inoculation. In addition, the inflammatory response to lipopolysaccharide in the cerebrospinal fluid can be reduced by the simultaneous inoculation of antibodies to tumor necrosis factor-a, IL-1b, or both

(,al 1990)- However, the use of antibodies against these cytokines does not completely abrogate the inflammatory response, suggesting that other mediators also play an important role.

Apart from the proinflammatory cytokines described above, anti-inflammmatory cytokines, such as interleukin 10 (IL-10) have recently been shown to be present in the cerebrospinal fluid of children with bacterial meningitis. IL-10 inhibits the production of chemokines by polymorphonuclear neutrophils, and downregulates production of intercellular adhesion molecule 1 (ICAM1) as well as chemoattractant proteins by endothelial cells. The significance of IL-10 and other host-produced anti-inflammatory agents in bacterial meningitis has not yet fully been elucidated.

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