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Review
Structural pathways for macromolecular
and cellular transport across the blood-brain barrier during
inflammatory conditions. Review
A.S. Lossinsky1 and R.R. Shivers2
1Immunohistochemistry and Electron Microscopy
Laboratories, Neural Engineering Program, Huntington Medical
Research Institutes, Pasadena, California, USA and 2Department
of Biology, University of Western Ontario, London, Ontario, Canada
Offprint requests to: Dr. Albert S. Lossinsky, Head, Immunohistochemistry
and Scanning Electron Microscopy Laboratories, Neural Engineering
Program, Huntington Medical Research Institutes, 734 Fairmount
Avenue, Pasadena, California, 91105, USA. Fax: (626) 397-5850.
e-mail: ALossinsky@aol.com
Summary. This
review presents an overview of the highlights of major concepts
involving the anatomical routes for the transport of macromolecules
and the transmigration of cellular elements across the blood-brain
barrier (BBB) during inflammation. The particular focus will
include inflammatory leukocytes, neoplastic cells and pathogenic
microorganisms including specific types of viruses, bacteria
and yeasts. The experimental animal models presented here have
been employed successfully by the authors in several independent
experiments during the past twenty-five years for investigations
of pathologic alterations of the BBB after a variety of experimentally
induced injuries and inflammatory conditions in mammalian and
non-mammalian animal species. The initial descriptions of endothelial
cell (EC) vesicles or caveolae serving as mini-transporters of
fluid substances essentially served as a springboard for many
subsequent discoveries during the past half century related to
mechanisms of uptake of materials into ECs and whether or not
pinocytosis is related to the transport of these materials across
EC barriers under normal physiologic conditions and after tissue
injury.
In the mid-1970's, the authors of this review independently applied
morphologic techniques (transmission electron microscopy-TEM),
in conjunction with the plant protein tracer horseradish peroxidase
(HRP) to investigate macromolecular transport structures that
increased after the brain and spinal cord had been subjected
to a variety of injuries. Based on morphologic evidence from
these studies of BBB injury, the authors elaborated a unique
EC system of modified caveolae that purportedly fused together
forming transendothelial cell channels, and later similar EC
profiles defined as vesiculo-canalicular or vesiculo-tubular
structures (VTS, Lossinsky, et al., 1999). These EC structures
were observed in association with increased BBB permeability
of tracers including exogenously injected HRP, normally excluded
from the intercellular milieu of the CNS. Subsequent studies
of non-BBB-type tumor ECs determined that the EC VTS and other
vesicular structures were defined by others as vesiculo-vacuolar
organelles (VVOs, Kohn et al., 1992; Dvorak et al., 1996). Collectively,
these structures appear to represent a type of anatomical gateway
to the CNS likely serving as conduits. However, these CNS conduits
become patent only in damaged ECs for the passage of macromolecules,
and purportedly for inflammatory and neoplastic cells as well
(Lossinsky et al., 1999). In this review, we focus attention
on the similarities and differences between caveolae, fused racemic
vesicular bundles, endothelial tubules and channels (VTS and
the VVOs) that are manifest in normal, non-BBB-type blood vessels,
and in the BBB after injury. This review will present evidence
that the previous studies by the authors and other researchers
established a framework for subsequent transmission (TEM), scanning
(SEM) and high-voltage electron microscopic (HVEM) investigations
concerning ultrastructural, ultracytochemical and immunoultra-strutural
alterations of the cerebral ECs and the mechanisms of the BBB
transport that occurs after CNS injury.
This review is not intended to include all of the many observations
that might be included in a general historical overview of the
development of the EC channel hypothesis, but it will discuss
several of the major contributions. We have attempted to present
some of the structural evidence that supports our early contributions
and those made by other investigators by highlighting major features
of these EC structures that are manifest in the injured BBB.
We have focused on currently established concepts and principles
related to mechanisms for the transendothelial transport of macromolecules
after CNS injury and also offer a critical appraisal of some
of this literature. Finally, we describe more recent concepts
of transBBB avenues for viruses, including HIV-1, bacterial and
mycotic organisms, as well as inflammatory and neoplastic cell
adhesion and migration across the injured mammalian BBB. Data
from studies of EC-related adhesion molecules, both from the
literature and from the author's experimental results and observations
made in other laboratories, as well as from personal communications
underscore the importance of the adhesion molecules in facilitating
the movement of leukocytic, neoplastic cell and human pathogens
across the BBB during inflammatory and neoplastic events.
Exciting, ongoing clinical trials are addressing possible therapeutic
intervention in neuroinflammatory diseases, including multiple
sclerosis, by blocking certain glycoprotein adhesion molecules
before cells have the ability to adhere to the ECs and migrate
across the BBB. Approaches whereby inflammation may be reduced
or arrested using anti-adhesion molecules, by restructuring EC
cytoskeletal, filamentous proteins, as well as remodeling cholesterol
components of the modified VTS are discussed in the context of
developing future therapies for BBB injury and inflammation.
Understanding new concepts about the mechanism(s) by which inflammatory
cells and a variety of pathogenic microorganisms are transported
across the BBB can be expected to advance our understanding of
fundamental disease processes. Taken together, the literature
and the author's experiences during the past quarter of a century,
will hopefully provide new clues related to the mechanisms of
transendothelial cell adhesion and emigration across the injured
BBB, issues that have been receiving considerable attention in
the clinical arena. Learning how to chemically modulate the opening
and/or closure of EC VTS and VVO structural pathways, or junctional
complexes prior to cellular or microorganism adhesion and breaching
the BBB presents challenging new questions in modern medicine.
Future studies will be critically important for the development
of therapeutic intervention in several human afflictions including
traumatic brain and spinal cord injuries, stroke, cancer, multiple
sclerosis and conditions where the immune system may be compromised
including HIV infection, infantile and adult meningitis. Histol.
Histopathol. 19, 535-564 (2004)
Key words: Leukocyte
migration, Blood-brain barrier, Endothelial cells, Vesiculo-canalicular
structures, VTS, Vesiculo-vacuolar organelles, VVOs horseradish
peroxidase
DOI: 10.14670/HH-19.535
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