benzyloxycarbonylvalyl-alanyl-aspartyl-fluoromethyl-ketone and Meningitis--Pneumococcal

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.

Topics: Amino Acid Chloromethyl Ketones; Animals; Brain; Caspase 1; Caspase Inhibitors; Central Nervous System Diseases; Cerebrospinal Fluid; Cysteine Proteinase Inhibitors; Interleukin-1; Lipid Peroxides; Lung; Meningitis, Pneumococcal; Mice; Mice, Knockout; Rats; Up-Regulation