Biology Reference
In-Depth Information
improved outcomes corresponded to a decreased number of pericontusional apoptotic
neurons and altered cortical cytokine production. A marked enhancement of TNF
was measured in both the injured and uninjured
lpr
mice, implicating TNF as a neu-
rotrophic mediator in recovery after TBI (Ziebell et al., unpublished observations).
The relevance of Fas in human TBI is indicated by several research groups' detec-
tion of sustained elevation of soluble Fas and Fas ligand in the cerebrospinal fluid
(CSF) of severely injured patients
[25,26]
. Interestingly, in pediatric TBI, higher con-
centrations of the anti-apoptotic factor Bcl-2 measured in CSF correlated with better
outcomes
[27]
. This group also showed that expression of apoptotic factors was asso-
ciated with neuronal cell death in adult TBI brain tissue. Specifically, an increase in
Bcl-2, cleavage of caspase-1, up-regulation and cleavage of caspase-3, and DNA frag-
mentation were found in cells having both apoptotic and necrotic morphologies
[28]
.
Although apoptosis and inflammation were previously considered to be inde-
pendent molecular cascades, evidence to date suggests a close link between Fas-
mediated cell death and cytokines, particularly related to the molecular structure and
role of the Fas/Fas ligand and TNF/receptor protein systems. For example, both Fas
and one of the two TNF receptors (p55) are type I transmembrane members of the
TNF/NGF receptor superfamily, and share homologous sequences in the extracellular
regions
[29,30]
. In addition to its role in apoptosis, Fas displays some neuroimmuno-
modulatory functions. In fact, Fas ligation on monocytes and macrophages induces a
pro-inflammatory cytokine response, resulting in potent neutrophil chemoattractant
bioactivity
[31]
. Likewise, the cytokines interleukin-(IL)-1, IL-6, TNF, and inter-
feron gamma had the ability to enhance constitutive Fas and Fas ligand expression in
cultured human astrocytes
[32]
. Taken together, these studies substantiate the com-
plex relationship between inflammation and the pathways of cell apoptosis, indicat-
ing that more work is required to fully elucidate the molecular mechanisms involved
in neuronal cell death secondary to TBI.
10.4 Cellular Inflammatory Response and Axonal Damage
The complex inflammatory responses elicited in the injured brain constitute distinct
and well-ordered stages of cell activation and immune mediator production. The
breakdown of the BBB that occurs rapidly after TBI allows the transmigration first of
neutrophils, then of macrophages and, in limited amounts, lymphocytes. All rodent
models of focal cortical damage have consistently reported a peak of neutrophils
accumulated in and around the lesion by 1 day
[17,33]
, whereas a massive infiltration
of resident microglia and blood macrophages does not reach a peak until 4-7 days
after TBI
[17]
.
The role of infiltrated neutrophils in contributing to secondary brain damage is
controversial. Some studies attribute a detrimental role to neutrophils in relation to
BBB function, because after activation these cells sustain inflammation and oxidative
stress via the release of reactive oxygen species that damage cell membranes, pro-
teins, and DNA. However, other work has demonstrated that depletion of neutrophils
in a TBI model does not alter the extent of edema in the injured hemisphere or the
