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Mol Med. 2001 Apr;7(4):219-29.

Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation.

Author information

1
Department of Neurology, The Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. siren@em.mpg.de

Abstract

BACKGROUND:

We have proposed that an increased interaction between monocyte/macrophages and blood vessel endothelium predisposes subjects to strokes. The effect of chronic monocyte activation on the development of cerebral infarcts was thus studied in rats after provocation of a modified local Swartzman reaction, in brain vasculature.

MATERIALS AND METHODS:

Two weeks after an IV bolus of bacillus Calmette-Guérin (BCG), we studied spontaneous superoxide production, integrin expression, endothelial adhesion of monocytes and the neurological symptoms, brain histology, and cytokine immunoreactivity after a provocative dose of LPS (30-300 microg/rat i.c.v.).

RESULTS:

Monocyte migration into the brain was stimulated by BCG priming. The incidence of paralysis and death in response to LPS was markedly increased in BCG-primed rats. Histological evaluation of the brains of neurologically impaired and moribund animals revealed intravascular thrombosis and pale and hemorrhagic infarcts. Infiltrates of leukocytes expressing immunoreactive IL-1:, IL-6, and TNF-alpha were found around blood vessels, cerebral ventricles, and meninges, and were accompanied by a profound microglial expression of IL1P, endothelial expression of IL-6, and expression of TNF-alpha and TNF-R 1 in glia and neurons of cortex and hippocampus. Treatment (2 x 100 microg/10 ,I, i.c.v.) with recombinant human (rh-)TNF 55kDa receptor completely prevented, and treatment with rh-IL- I receptor antagonist significantly decreased the incidence of paralysis and death in response to BCG + LPS. The improvement of neurological symptoms was accompanied by reduced histological damage and supppression of IL-1P/ expression in the brain tissue.

CONCLUSIONS:

The data demonstrate that chronic monocyte activation predisposes subjects to thrombosis and hemorrhage via an exaggerated release of proinflammatory cytokines.

PMID:
11471566
PMCID:
PMC1950036
[Indexed for MEDLINE]
Free PMC Article

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