KOEDEL U, WINKLER F, ANGELE B, FLAVELL RA, FONTANA A, PFISTER HW; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 46.

Dept. of Neurology, Munich, Germany

The caspase inhibitor z-VAD-FMK was reported to attenuate meningeal inflammation and pathophysiologic alterations in animal models of pneumococcal meningitis (PM). However, the interpretation of these results is problematic because z-VAD-FMK is capable of inhibiting caspases with divergent biological activites (e.g., caspase-1 and -3). To explore the role of caspase-1 in PM we used mice deficient in this enzyme. Meningitis was induced by intracisternal injection of live pneumococci. Twenty four hours later, intracranial pressure (ICP), cerebrospinal fluid leukocyte count (CSF WBC), and blood-brain barrier (BBB) permeability were determined. Additionally, brain homogenates were analyzed for inflammatory mediators and lipid peroxidation products (LPP; markers for tissue injury). The following experimental groups were investigated: (1) infected C57BL/6 mice (n=9); (2) infected 129SvxC57BL/6 mice (n=6); (3) infected, caspase-1-deficient mice (Cas1-/-; n=8); (4) C57BL/6 controls (injected with phosphate-buffered saline; n=4); (5) Cas1-/- controls (n=4). Pneumococcal infection led to a significant increase in ICP, CSF WBC, BBBP, and brain LPP levels in both wild type strains investigated. RT-PCR analysis revealed increased brain mRNA levels of caspase-1, MIP-1a , MIP-2, and iNOS. By using ELISA, elevated brain concentrations of IL-1b and TNF-a (but not IL-18) were detected. Infected Cas1-/- mice had significantly lower ICP values (9 +/- 2 mmHg vs. 17 +/- 3 and 18 +/- 3 mmHg in group 1 and 2), CSF WBC, and an attenuated BBB disruption. This effect was associated with a reduced expression of cytokines, chemokines, and iNOS, as well as with decreased brain LPP levels. Thus, this study points at a central role of caspase-1 in the exaggeration of inflammation and tissue injury in PM.KEYWORDS: Caspase; Meningitis; Mice

Publication Types:

• Meeting Abstracts

Keywords:

• Amino Acid Chloromethyl Ketones
• Animals
• Blood-Brain Barrier
• Brain
• Caspase 1
• Caspases
• Chemokine CXCL2
• Chemokines
• Cytokines
• Inflammation
• Intracranial Pressure
• Meningitis, Pneumococcal
• Mice
• Mice, Inbred C57BL
• Monokines
• Nitric Oxide Synthase
• RNA, Messenger
• Reverse Transcriptase Polymerase Chain Reaction
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• cerebrospinal fluid
• deficiency

Other ID:

• GWAIDS0010923

UI: 102248421

From Meeting Abstracts