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Intravenous immunoglobulins prevent breakdown of the blood-brain barrier in experimental sepsis


The effect of intravenous immunoglobulin preparations - immunoglobulin G (IgG), immunoglobulin G enriched with IgA and IgM (IgGAM) - on blood-brain barrier (BBB) integrity and survival rate was comparatively investigated in septic rats.


Sepsis was induced by cecal ligation and perforation (CLP) in Sprague-Dawley rats. The animals received either IgG (250 mg/kg, intravenously) or IgGAM (250 mg/kg, intravenously) 5 minutes before CLP surgery. All rats were observed for behavioral changes for 24 hours after CLP operation. To show the alterations in BBB integrity, Evans blue (EB; 69 kDa) dye extravasation was determined for quantitative measurement of BBB permeability, and horseradish peroxidase (HRP; 40 kDa) extravasation was evaluated to provide ultrastructural evidence for the transport pathways involved in BBB permeability. Immunohistochemistry was performed to show the alterations in immunoreactivity for tight junction protein occludin.


A high mortality rate (34%) was noted in septic animals and the mortality rate was decreased to 15% and 3% by IgG and IgGAM, respectively. Both IgG and IgGAM alleviated the sickness behavior in septic rats and the animals were observed to be healthy and active. Increased extravasation of EB dye into brain tissue of septic animals was markedly decreased by both IgG and IgGAM. Occludin immunoreactivity remained essentially unchanged in all groups including CLP. In addition, strong staining for HRP was seen around vessels located in the cerebral cortex and the hippocampus in septic animals. Increased luminal and abluminal vesicles containing electron-dense HRP reaction product were noted in the cytoplasm of endothelial cells in the cerebral cortex and hippocampus of septic rats, emphasizing an increased BBB permeability predominantly by transendothelial route. In these animals, tight junctions were ultrastructurally intact suggesting that paracellular pathway of BBB is not responsible for the BBB breakdown in sepsis. Following IgG or IgGAM treatment, no ultrastructural evidence of leaky capillaries in brain was observed in septic animals indicating the blockade of the transcellular pathway.


The present study indicates that IgG and IgGAM improve the integrity of the BBB and inhibit CLP-induced sickness behavior in rats.

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Esen, F., Senturk, E., Ozcan, P. et al. Intravenous immunoglobulins prevent breakdown of the blood-brain barrier in experimental sepsis. Crit Care 14 (Suppl 1), P24 (2010).

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  • Tight Junction
  • Evans Blue
  • Sickness Behavior
  • Septic Animal
  • Ultrastructural Evidence