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 μg/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-1β, IL-6, and TNF-α were found around blood vessels, cerebral ventricles, and meninges, and were accompanied by a profound microglial expression of IL1β, endothelial expression of IL-6, and expression of TNF-α and TNF-R1 in glia and neurons of cortex and hippocampus. Treatment (2 × 100 μg/10 μ1, i.c.v.) with recombinant human (rh-)TNF 55kDa receptor completely prevented, and treatment with rh-IL-1 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-1β 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.
CITATION STYLE
Sirén, A. L., McCarron, R., Wang, L., Garcia-Pinto, P., Ruetzler, C., Martin, D., & Hallenbeck, J. M. (2001). Proinflammatory cytokine expression contributes to brain injury provoked by chronic monocyte activation. Molecular Medicine, 7(4), 219–229. https://doi.org/10.1007/bf03401841
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