Ultrastructural localization of albumin transport across the cerebral microvasculature during experimental meningitis in the rat.
Injury to the blood brain barrier (BBB) is a fundamental sequela of bacterial meningitis, yet the precise mechanism facilitating exudation of albumin across the endothelium of the cerebral microvasculature remains conjectural. After intracisternal inoculation of Escherichia coli (0111:B4) lipopolysaccharide in rats to elicit a reversible meningitis and BBB injury, we utilized in situ tracer perfusion and immunolabeling procedures to identify by transmission electron microscopy the precise topography and microvascular exit pathway(s) of bovine serum albumin (BSA). Results revealed that during meningitis there was: (a) an inducible increase in immunodetectable monomeric BSA binding to the luminal membrane of all microvascular segments in the pia-arachnoid and superficial brain cortex; (b) similar uptake of both colloidal Au-BSA (as well as monomeric BSA) by plasmalemmal vesicles but no detectable transcytosis to the abluminal side; and (c) predominant exit of both perfused Au-BSA and immunodetectable monomeric BSA through open intercellular junctions of venules in the pia-arachnoid. This was corroborated in separate experiments documenting focal pial venular leaks of in situ perfused 0.01% colloidal carbon black during experimental meningitis. These results provide precise localization of BBB injury in meningitis to meningeal venules, confirm a paracellular exit pathway of albumin via open intercellular junctions, and suggest an injury mechanism amenable to specific therapeutic intervention.
Quagliarello
V J
VJ
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Ma
A
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Stukenbrok
H
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Palade
G E
GE
D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier; D002244:Carbon; D004926:Escherichia coli; D007150:Immunohistochemistry; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D008581:Meningitis / Q000378:metabolism* / Q000473:pathology; D008833:Microcirculation / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D012710:Serum Albumin, Bovine / Q000378:metabolism*
D008070:Lipopolysaccharides; D012710:Serum Albumin, Bovine; D002244:Carbon