Detachment of Brain Pericytes from the Basal Lamina is Involved in Disruption of the Blood–Brain Barrier Caused by Lipopolysaccharide-Induced Sepsis in Mice

Abstract

The blood-brain barrier (BBB) is highly restrictive of the transport of substances between blood and the central nervous system. Brain pericytes are one of the important cellular constituents of the BBB and are multifunctional, polymorphic cells that lie within the microvessel basal lamina. The present study aimed to evaluate the role of pericytes in the mediation of BBB disruption using a lipopolysaccharide (LPS)-induced model of septic encephalopathy in mice. ICR mice were injected intraperitoneally with LPS or saline and were sacrificed at 1, 3, 6, and 24 h after injection. Sodium fluorescein accumulated with time in the hippocampus after LPS injection; this hyperpermeability was supported by detecting the extravasation of fibrinogen. Microglia were activated and the number of microglia increased with time after LPS injection. LPS-treated mice exhibited a broken basal lamina and pericyte detachment from the basal lamina at 6-24 h after LPS injection. The disorganization in the pericyte and basal lamina unit was well correlated with increased microglial activation and increased cerebrovascular permeability in LPS-treated mice. These findings suggest that pericyte detachment and microglial activation may be involved in the mediation of BBB disruption due to inflammatory responses in the damaged brain.

C3-dependent mechanism of microglial priming relevant to multiple sclerosis

“…Because the BBB is likely to be intact in the primed CNS, and we show here that systemic C inhibition alone is not sufficient, such agents must be able to cross the barrier. Targeting the switch from primed to activated might be easier as the barrier is breached early in CNS inflammation (42,43). Therapies could be timed and targeted to reduce the impact of systemic insults on primed microglia in those at risk, for example, by giving them as prophylactic cover for surgery or as prompt interventions in systemic infection.…”

Systemic Lipopolysaccharide Compromises the Blood-Labyrinth Barrier and Increases Entry of Serum Fluorescein into the Perilymph

“…Rather, larger molecular weight reagents such as Evans blue, radioactive albumin and fluorescent-IgG have been used (Tachibana et al 1981;Kastenbauer et al 2001;Trune 1997). Others have measured the dye content of tissue homogenates, but this application in assessment of inner ear vascular permeability has been met with limited success (Rossner and Tempel 1966;Veszelka et al 2003;Awad 2006). When used in the inner ear, these techniques demonstrate shortcomings due to high levels of contamination from dyes that leach out of the cochlear vessels during tissue processing.…”

“…Traditional studies in the central nervous system have employed methods such as dye exclusion tests, radioactive tracers, as well as in vitro models to assess the integrity of the BLB and the BBB (Rossner and Tempel 1966;Wispelwey et al 1988;Zhang et al 2013). Agents such as Evans blue dye or fluoresceintagged molecules can be effective to determine sites of vascular leakage where there are large volumes of tissue that are sparsely vascularized (Nishioku et al 2009;Fernandez-Lopez et al 2012;He et al 2014).…”

“…Agents such as Evans blue dye or fluoresceintagged molecules can be effective to determine sites of vascular leakage where there are large volumes of tissue that are sparsely vascularized (Nishioku et al 2009;Fernandez-Lopez et al 2012;He et al 2014). However, the inner ear of the mouse is tiny, the vessels are in close proximity to the tissues and fluids of interest, and sectioning the inner ear and imaging those sections to determine the extent of dye extravasation from vessels into adjacent tissues can pose challenges of interpretation.…”

Cellular Mechanisms of MOF During Severe Sepsis and Septic Shock

“…BBB dysfunction is found in patients and rodent models of sepsis and causes increased infiltration of inflammatory cells and increased exposure of the brain to toxins (Nishioku et al, 2009). The BBB impairment may be caused by disruption of the normal interaction between endothelial cells, astrocytes and pericytes leading to increased pineocytosis and disruption of tight junctions.…”