Biology Reference
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infarct size
[34,35]
. Similarly, increased numbers of peripheral neutrophils induced
by the injection of granulocyte colony-stimulating factor caused an increase in BBB
damage; however, this did not alter the accumulation of neutrophils in the brain or
have any impact on edema, suggesting the involvement of other mechanisms in the
development of brain swelling after TBI
[36]
.
Essential for the adhesion and infiltration of neutrophils is the up-regulation of
cell adhesion molecules such as intracellular adhesion molecule (ICAM) at the BBB.
We had previously shown that the concentrations of soluble ICAM-1 in the CSF of
patients with severe TBI were associated with BBB dysfunction and the contusion
size measured on computer tomogram scans
[37]
. Animal experiments failed to sup-
port this relationship: the use of ICAM-1 knockout mice in a model of controlled
cortical impact injury reported no differences in the extent of neutrophil infiltration,
lesion size, or neurological outcome
[38]
. Furthermore, this lack of relationship is
supported by our animal studies wherein up-regulation of ICAM-1 in brain tissue fol-
lowing a cortical contusion in mice was maximal at 7 days—a late time point com-
pared to the peak in neutrophil infiltration observed at 24 hours
[39]
. Late expression
of ICAM-1 on cerebral vessels of rats subjected to diffuse axonal injury, along with
the absence of brain neutrophil accumulation, is a further argument against the
involvement of this molecule in leukocyte transmigration
[40]
. An alternative func-
tion for ICAM-1 was proposed by
in vitro
experiments performed in our laboratory
demonstrating that both astrocytes and cerebral endothelial cells stimulated with
recombinant soluble (s)ICAM-1 induce the release of the neutrophil chemokine
MIP-2, the murine homologue of human IL-8
[39]
. In addition, a synergistic effect
was shown when both cultures were exposed simultaneously to sICAM-1 and TNF,
demonstrating alternative signaling pathways. These data indicate that by promoting
chemokine production, ICAM-1 may sustain leukocyte activation and passage into
the injured brain.
Microglia
are the resident macrophages of central nervous system (CNS) paren-
chyma; they originate from the bone marrow during development of the nervous sys-
tem. The shape of these cells differs considerably in both health and disease states.
Microglia activation follows a specific pattern of morphological changes character-
ized by distinct combinations of surface molecules
[41]
. In a resting phase, they are
barely detectable by immunohistochemistry, and display a ramified morphology.
However, following stimulation microglia become fully activated and identical to
ameboid macrophages. Upon challenge, microglia secrete a large number of inflam-
matory cytokines, reactive oxygen species, and glutamate, and are rapidly stimulated
by serum proteins to display phagocytic function.
Using the closed head injury mouse model, our laboratory group demonstrated that
the presence of pericontusional microglia/macrophages persisted up to 4 weeks; how-
ever, the area of cell spread around the lesion at this late time point was significantly
reduced
[42]
(
Figure 10.1
). These cells appear heavily vacuolated, having phagocy-
tosed the cell debris of the dead tissue. When neuronal staining is compared with astro-
glial immunohistochemistry at 4 weeks postinjury, it appears that reactive astrocytes
surround the lesion core, which is completely devoid of neurons. Among all brain
cells, microglia are believed to contribute most significantly to neurotoxic secondary
