Quagliarello V J, Ma A, Stukenbrok H, Palade G E
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
J Exp Med. 1991 Sep 1;174(3):657-72. doi: 10.1084/jem.174.3.657.
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.
血脑屏障（BBB）损伤是细菌性脑膜炎的一个基本后遗症，然而，促进白蛋白透过脑微血管内皮渗出的确切机制仍存在推测。在大鼠脑池内接种大肠杆菌（0111:B4）脂多糖以引发可逆性脑膜炎和血脑屏障损伤后，我们利用原位示踪剂灌注和免疫标记程序，通过透射电子显微镜确定牛血清白蛋白（BSA）的确切拓扑结构和微血管出口途径。结果显示，在脑膜炎期间存在：（a）免疫可检测到的单体BSA与软脑膜 - 蛛网膜和浅表脑皮质中所有微血管段的腔面膜结合的诱导性增加；（b）血浆膜囊泡对胶体金 - BSA（以及单体BSA）的类似摄取，但未检测到向腔外侧的跨细胞转运；（c）灌注的金 - BSA和免疫可检测到的单体BSA主要通过软脑膜 - 蛛网膜中小静脉的开放细胞间连接排出。在单独的实验中得到了证实，这些实验记录了实验性脑膜炎期间原位灌注的0.01%胶体炭黑的局灶性软脑膜静脉渗漏。这些结果将脑膜炎中血脑屏障损伤精确地定位到脑膜小静脉，证实了白蛋白通过开放细胞间连接的细胞旁出口途径，并提出了一种适合特定治疗干预的损伤机制。
