Biology Reference
In-Depth Information
corpus callosum
[45]
. Surprisingly, even in the most severe diffuse injury (450 g from
2 m) cell death is hardly detectable in the brain, although the animals show protracted
motor impairment in sensorimotor tests as well as the rotarod
[40,46]
. This may be
explained by the dysfunction of the synaptic transmission at the damaged axons,
which impairs neurological function, rather than a significant loss of neuronal cell
bodies. Astroglial reactivity also occurs relatively early even in the milder form of
injury (250 g from 2 m), and persists for at least 2 weeks after injury
[45]
.
10.5 Cerebral Cytokine Network
The aseptic humoral inflammatory cascade evolving in the injured brain is milder
than the reaction typical of an infectious disease elicited in either the CNS or periph-
eral organs. This is likely due to the refractory nature of the brain, once considered
an “immune privileged site,” which dampens any immune reaction in order to mini-
mize inflammatory-mediated tissue damage. This conclusion is supported by experi-
ments showing that higher doses of the endotoxin lipopolysaccharide (LPS) injected
in the brain are required to induce brain cytokine production, as compared to sub-
cutaneous inoculation
[47]
. Similarly,
in vitro
, higher concentrations of LPS are clas-
sically used to stimulate cultured astrocytes or microglia, as opposed to stimulation
of peripheral macrophages. The ultimate role of cerebral inflammation after TBI is
to repair the damage, but there is sufficient evidence to suggest that when protracted
over time or when released at high concentrations, cytokine release in the injured
brain can generate further harm.
Cytokines
are small peptides with a molecular weight of approximately 20 kDa.
They are produced by all cells of the CNS in a complex network to regulate a variety
of cellular functions, including activation, migration, differentiation, regeneration,
and death. The expression of selected and specific cytokine receptors at the cere-
bral endothelium suggests that cytokines can cross the BBB from the bloodstream
to the brain and vice versa, via a saturable carrier-mediated system
[48]
. Cytokines
themselves can disrupt the BBB and be produced by endothelial cells and astrocytes
located at the barrier. This transport system renders the brain heavily vulnerable to
systemic infections (for instance, encephalopathy, which is often encountered in sep-
tic patients). In contrast, cytokines produced in the brain, such as IL-6, may influ-
ence the function of peripheral organs (e.g., the liver) by inducing the posttraumatic
acute phase reaction
[49]
. This continuum demonstrates that isolation of the brain by
the BBB is limited and subject to specific conditions in health and disease.
Over the past years, it has been established that cerebral inflammation elicited
following TBI plays a dual function: it can exacerbate tissue damage, but it can also
promote the processes of repair
[11,50-52]
. Summarizing the large body of work
produced in the past two decades is not an easy task. Therefore, this chapter focuses
on the most relevant studies, with an update on the current literature concerning this
topic.
Table 10.1
summarizes some of the pivotal studies, beginning with the early evi-
dence that cytokines are synthesized in the brain of animals subjected to various forms
of TBI, to the first substantiation of cerebral cytokine release into human ventricular
