Differential expression of nitric oxide synthases in bacterial meningitis:Role of the inducible isoform for blood-brain barrier breakdown

The aim of the study was to determine the differential expression of nitric oxide (NO) synthase (NOS) isoforms and the pathophysiologic relevance of i nducible NOS (iNOS) in experimental pneumococcal meningitis. By use of reve rse transcription-polymerase chain reaction analysis, immunohistochemistry, and Western blotting, increased brain mRNA and increased protein levels of endothelial NOS (eNOS) and iNOS were detected 24 h after intracisternal pn eumococcal inoculation. In iNOS-deficient mice, disruption of the blood-bra in barrier (BBB) was significantly reduced, compared with that in wild-type mice. This beneficial effect of iNOS deficiency was associated with a lack of nitrotyrosine immunoreactivity. Furthermore, brain protein levels of in terleukin (IL)-1 beta IL-6, and tumor necrosis factor-alpha and brain mRNA levels of macrophage inflammatory protein (MIP)-1 alpha and MIP-2 were sign ificantly reduced in infected animals lacking iNOS. These findings suggest that (1) not only iNOS but also eNOS is up-regulated in the acute phase of experimental bacterial meningitis, and (2) iNOS-derived NO contributes to p eroxynitrite formation and BBB breaching in this disease.