-
BadBad
Cell Survival
P Pro-death via some
PKC isoforms
PKB
FIGURE 8-6
Cartoon showing the role of important survival signal-mediated kinase activation in promoting neuronal survival. Phospho-inositide 3-kinase (PI3-K), protein kinase B (PKB), and protein kinase A (PKA) pathways are involved. PKB affects survival by a number of mechanisms including the phosphorylation and inactivation of the pro-death mediator Bad. Phosphorylation of Bad results in its dissociation from Bcl-xL inhibiting cell death. CAMP-mediated activation of PKA can also lead to for-mation of the transcription factor “cAMP response element binding protein” (CREB), which also promotes cell survival
TBI: PATHOBIOLOGY 89
addressed by surgical evacuation (116). However, there are several important mechanisms that are more uni-formly involved in the development of intracranial hypertension. These are related to either brain swelling from vasogenic edema, astrocyte swelling, and an increase in tissue osmolar load, or vascular dysregula-tion with swelling secondary to an increase in cerebral blood volume (CBV).
Recent data suggest that brain swelling after severe TBI results from edema rather than increased CBV.
Marmarou et al. (117) measured both CBV and brain water in adults with TBI. Using a dye indicator technique (coupled to CT) to measure CBV and magnetic resonance imaging [MRI] to quantify brain water, increases in brain water were commonly observed, but were generally asso-ciated with reduced (not increased) CBV (Figure 8-8).
Thus, edema rather than increased CBV appears to be the predominant contributor to cerebral swelling after TBI. Both cytotoxic and vasogenic edema may play impor-tant roles in cerebral swelling. However, our traditional concept of cytotoxic and vasogenic edema is evolving.
There appear to be four putative mechanisms for edema formation in the injured brain. First, vasogenic edema may form in the extracellular space as a result of blood-brain barrier (BBB) disruption. Second, cellular swelling can be produced in two ways. Astrocyte swelling can occur as part of the homeostatic uptake of substances such as glutamate.
Glutamate uptake is coupled to glucose utilization via a sodium/potassium ATPase, with sodium and water accu-mulation in astrocytes. Swelling of both neurons and other cells in the neuropil can also result from ischemia- or trauma-induced ionic pump failure. Finally, osmolar swelling may also contribute to edema formation in the extracellular space, particularly in contusions. Osmolar swelling, however, is actually dependent on an intact BBB or an alternative solute barrier.
Cellular swelling may be of greatest importance.
Using a model of diffuse TBI in rats, Barzo et al. (118) applied diffusion-weighted MRI to localize the increase in brain water. A decrease in the apparent diffuse coeffi-cient after injury suggested predominantly cellular swelling, rather than vasogenic edema, in the development FIGURE 8-7
Reactive axonal swellings have been proposed to result from focal axolemmal disruption, ionic shifts and neurofilamentous com-paction at site (A) results in a reactive swelling at site (B) in an upstream region of the axon. At the site of ionic influx, neuro-filamentous compaction and mitochondrial swelling is seen (C). Neurofilament compaction is associated with neurofilament sidearm loss (D). Obstructed axonal transport results in upstream axonal enlargement, neurofilament misalignment, organelle accumulation, and formation of the typical reactive axonal swelling (E)
of intracranial hypertension. Cellular swelling may be of even greater importance in the setting of TBI with a sec-ondary hypoxemic-ischemic insult (119).
Katayama et al. (120) also suggested that the role of BBB in the development of post-traumatic edema may have been overstated—even in the setting of cerebral contusion.
One intriguing possibility is that as macromolecules are degraded within injured brain regions, the osmolar load in the contused tissue increases. As the BBB reconstitutes (or as other osmolar barriers are formed), a considerable osmolar driving force for the local accumulation of water develops, resulting in the marked swelling so often seen in and around cerebral contusions (Figure 8-9).
In some cases, increases in CBV can be seen after TBI and contribute to intracranial hypertension. When an increase in CBV is seen, it may result from local increases in cerebral glycolysis “hyperglycolysis” as described by Bergsneider et al. (22). In regions with increases in gluta-mate levels, such as in contusions, increases in glycolysis are observed because astrocyte uptake of glutamate is cou-pled to glycolysis rather than oxidative metabolism. Recall that oxidative metabolism is generally depressed by
~50percent in comatose victims of severe TBI in the ICU (20). Hyperglycolysis results in a marked local increase in cerebral glucose utilization with a coupled increase in CBF and CBV and resultant local brain swelling. A detailed dis-cussion of this topic is beyond the scope of this chapter.
As MRI and MR-spectroscopic methods continue to develop and become applied to critically ill patients (121) our “black box” knowledge of the mechanisms involved in cerebral swelling should greatly advance. It must be remembered that although neuronal and axonal injury are key downstream events in the evolution of damage after severe TBI, brain swelling and resultant intracra-nial hypertension is still the principal target for titration of therapy in the ICU.
INFLAMMATION AND REGENERATION There appear to be both acute detrimental and sub-acute/chronic beneficial aspects of inflammation. There is robust acute inflammation after TBI. This has been shown in models of TBI (122–124), and in adult patients (125–128). NF-B (129), TNF (130, 131), IL-1 (132, 133), eicosanoids (134), neutrophils (123,135), and macrophages (136,137) contribute to both secondary damage and repair.
Markers of inflammation after TBI have been assessed in humans using two general strategies, (i) exam-ination of inflammation in contused brain tissue resected from patients with refractory intracranial hypertension, and (ii) study of mediator levels in CSF. Consistent with a role for IL-1 in the evolution of tissue damage in FIGURE 8-8
The percentage change in brain water content as assessed by MRI and cerebral blood volume (CBV) as measured by CT and indicatory dilution technique in 109 studies of adults with TBI. Brain water is increased and CBV is reduced in adults with severe TBI. Reprinted from the work of Marmarou et al. (121) with permission
TBI: PATHOBIOLOGY 91
human TBI, Clark et al. (54) performed western analysis of brain samples resected from adults with refractory intracranial hypertension secondary to severe contusion.
Interleukin-1-converting enzyme (ICE) was activated, as evidenced by specific cleavage in patients with TBI. ICE activation is critical to the production of IL-1. ICE
acti-vation was not detected in patients that died of non-CNS etiologies (Figure 8-10). This supports the production of IL-1, a pivotal pro-inflammatory mediator, in the trau-matically injured brain in humans.
Studies of CSF further support a role for inflamma-tion in TBI. Marion et al. (126) demonstrated increases FIGURE 8-9
Schematic based on hypothesis of Katayama et al. (120) suggesting that as the osmolar load increases (breakdown of macro-molecules in the region of contusion necrosis), a considerable driving force develops for the accumulation of water, resulting in the secondary swelling so often seen in and around cerebral contusions
FIGURE 8-10
Evidence for activation of IL-1 converting enzyme (ICE) activation in cerebral contusions resected from adult patients with severe TBI and refractory intracranial hypertension. Western analysis demonstrating cleavage of the intact 45 kD pro-caspase-1 to the 10 kD fragment in each of eight victims of severe TBI but in none of 6 control brain samples from patients that died of non-CNS causes. Reprinted from Clark et al. (63) with permission
in IL-1 in CSF after severe TBI in adults. These increases were attenuated by the use of moderate therapeutic hypothermia. Similarly, there are increases of a number of cytokines in CSF after severe TBI including IL-6, and IL-8 (128,138). Contusion and local tissue necrosis appear to be important to trigger neutrophil influx with resultant secondary tissue damage (123). Neutrophil influx is accompanied by increases in inducible nitric oxide synthase (iNOS) levels in brain (124) and is fol-lowed by macrophage infiltration, which peaks between 24–72 hours after injury (139). Macrophage infiltration and the differentiation of endogenous microglia into res-ident macrophages may signal the link between inflam-mation and regeneration, with elaboration of a number of trophic factors (i.e., nerve growth factor (NGF), nitrosothiols, vascular endothelial growth factor) (133, 138,140,141).
Kossmann et al (138) reported a link between IL-6 production and the production of neurotrophins, such as NGF. Cultured astrocytes treated with either IL-6, IL-8 or CSF from brain-injured adults, produced NGF.
Cytokine production after TBI may be important to neu-ronal plasticity and repair, as discussed below.
Studies in models of TBI (131, 142) suggest benefi-cial aspects of inflammation on long-term outcome. Mice deficient in TNF exhibit improved functional outcome (versus wild-type) early after TBI. However, the long-term consequences of TNF deficiency on outcome are detri-mental (131). Similarly, despite a detridetri-mental role for iNOS in the initial 72 h posttrauma (143), iNOS deficient mice demonstrated impaired long-term outcome vs con-trols (142). iNOS is important in wound healing and iNOS-derived nitrosylation of proteins may play a role (141,144). Regeneration and plasticity play important roles in mediating beneficial long-term effects on recov-ery, and these responses are linked to inflammation.
The contribution of the inflammatory response to TBI remains to be determined. Although there are a few promis-ing reports in models of the use of anti-inflammatory therapies in TBI and ischemia (targeting IL-1, ICE, and TNF) it is unclear whether anti-inflammatory therapies will improve outcome after clinical TBI. If inhibition of the inflammatory response is considered, exacerbation of infection risk must also be anticipated (145). Also, the link between inflammation and regeneration must be recognized.
CONCLUSIONS
Mechanisms involved in the evolution of secondary brain injury after TBI have been reviewed. Particular attention has been paid to studies at the bedside. Our understand-ing of the biochemical, cellular, and molecular responses has progressed—particularly with the application of
molecular biology methods to human materials. Addi-tional details on these mechanisms have also been reviewed in a companion article to this chapter which addresses the unique setting of pediatric TBI (146). Future investigation should integrate these findings with bedside physiology and an improved assessment of outcome. Finally, novel imaging and diagnostic methods, particularly MRI and MRS must be coupled with biochemical and molecular methods to clarify the mechanisms involved in secondary damage and the local effects of novel therapies.
ACKNOWLEDGEMENTS
The authors dedicate this chapter to the late Dr. Peter Safar for his vision and inspiration. We thank the National Institutes of Health/NINDS NS38087 (PMK), NS38620 (RSBC), NS 40049 (LJ) and NS30318 (PMK, RSBC), Center for Disease Control/University of Pitts-burgh CIRCL (PMK), and the Laerdal Foundation for supporting this work. We thank Marci Provins and Fran Mistrick for preparation of the manuscript.
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