Mario Rancan

Inflammatory response in acute traumatic brain injury: a double-edged sword

Inflammation is an important part of the pathophysiology of traumatic brain injury. Although the central nervous system differs from the other organs because of the almost complete isolation from the blood stream mediated by the blood–brain barrier, the main steps characterizing the immune activation within the brain follow a scenario similar to that in other organs. The key players in these processes are the numerous immune mediators released within minutes of the primary injury. They guide a sequence of events including expression of adhesion molecules, cellular infiltration, and additional secretion of inflammatory molecules and growth factors, resulting in either regeneration or cell death. The question is this: to what extent is inflammation beneficial for the injured brain tissue, and how does it contribute to secondary brain damage and progressive neuronal loss? This review briefly reports recent evidence supporting the dual, the beneficial, or the deleterious role of neuroinflammation after traumatic brain injury.

Role of cerebral inflammation after traumatic brain injury : A revisited concept

ABSTRACT— Neuroinflammation occuring after traumatic brain injury (TBI) is a complex phenomenon comprising distinct cellular and molecular events involving the injured as well as the healthy cerebral tissue. Although immunoactivation only represents a one of the many cascades initiated in the pathophysiology of TBI, the exact function of each mediator, activated cell types or pathophysiological mechanism, needs to be further elucidated. It is widely accepted that inflammatory events display dual and opposing roles promoting, on the one hand, the repair of the injured tissue and, on the other hand, causing additional brain damage mediated by the numerous neurotoxic substances released. Most of the date supporting these hypotheses derive from experimental work based on both animal models and cultured neuronal cells. More recently, evidence has been provided that a complete elimination of selected inflammatory mediators is rather detrimental as shown by the attenuation of neurological recovery. However, there are conflicting results reported on this issue which strongly depend on the experimental setting used. The history of immunoactivation in neurotrauma is the subject of this review article, giving particular emphasis to the comparison of clinical versus experimental studies performed over the last 10 years. These results also are evaluated with respect to other neuropathologies, which are years ahead as compared to the research in TBI. The possible reciprocal influence of peripheral and intrathecal activation of the immune system will also be discussed. To conclude, the future directions of research in the field of neurotrauma is considered.

S-100β Reflects the Extent of Injury and Outcome, Whereas Neuronal Specific Enolase Is a Better Indicator of Neuroinflammation in Patients With Severe Traumatic Brain Injury

It has been hypothesized that immunoactivation may contribute to brain damage and affect outcome after traumatic brain injury (TBI). In order to determine the role of inflammation after TBI, we studied the interrelationship of the immune mediators sICAM-1 and IL-6 with the levels of S-100β and neuronal specific enolase (NSE), both recognized markers of brain damage. In addition, the extent and type of cerebral injury and the neurological outcome were related to these measured markers of injury. An evident elevation of S-100β (range of means: 2.7-81.4 ng/mL) and NSE (range of means: 2.0-81.3 ng/mL) was observed in CSF of all 13 patients during the first 3 post-traumatic days and decreased over 2 weeks. In parallel, the production of sICAM-1 (range of means: 0.7-11.9 ng/mL) and IL-6 (range of means: 0.1-8.2 ng/mL) was also markedly enhanced in CSF. The CSF means of S-100β and NSE per patient correlated with IL-6 (r = 0.60, p < 0.05; and r = 0.64, p < 0.05, respectively), whereas the corresponding means in s...

Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury.

Proinflammatory cytokines are important mediators of neuroinflammation after traumatic brain injury. The role of interleukin (IL)-18, a new member of the IL-1 family, in brain trauma has not been reported to date. The authors investigated the posttraumatic release of IL-18 in murine brains following experimental closed head injury (CHI) and in CSF of CHI patients. In the mouse model, intracerebral IL-18 was induced within 24 hours by ether anesthesia and sham operation. Significantly elevated levels of IL-18 were detected at 7 days after CHI and in human CSF up to 10 days after trauma. Published data imply that IL-18 may play a pathophysiological role in inflammatory CNS diseases; therefore its inhibition may ameliorate outcome after CHI. To evaluate the functional aspects of IL-18 in the injured brain, mice were injected systemically with IL-18–binding protein (IL-18BP), a specific inhibitor of IL-18, 1 hour after trauma. IL-18BP—treated mice showed a significantly improved neurological recovery by 7 days, accompanied by attenuated intracerebral IL-18 levels. This demonstrates that inhibition of IL-18 is associated with improved recovery. However, brain edema at 24 hours was not influenced by IL-18BP, suggesting that inflammatory mediators other than IL-18 induce the early detrimental effects of intracerebral inflammation.

Central Nervous System–Targeted Complement Inhibition Mediates Neuroprotection after Closed Head Injury in Transgenic Mice

The role of intracerebral complement activation after traumatic brain injury remains unclear. In this study, the authors demonstrate that transgenic mice with astrocyte-targeted expression of the soluble complement inhibitor sCrry have a significantly reduced neurologic impairment and improved blood–brain barrier function after closed head injury compared with wild-type C57BL/6 littermates. This work further implicates the complement system as a participant in secondary progression of brain damage after head trauma and provides a strong rationale for future studies of posttraumatic pharmacologic complement inhibition.

Regulation of chemokines and chemokine receptors after experimental closed head injury.

The expression of the chemokines macrophage inflammatory protein (MIP)-2 and MIP-1α and of their receptors CXCR2 and CCR5 was assessed in wild type (WT) and TNF/lymphotoxin-α knockout (TNF/LT-α−/−) mice subjected to closed head injury (CHI). At 4 h after trauma intracerebral MIP-2 and MIP-1α levels were increased in both groups with MIP-2 concentrations being significantly higher in WT than in TNF/LT-α−/− animals (p < 0.05). Thereafter, MIP-2 production declined rapidly, whereas MIP-1α remained elevated for 7 days. Expression of CXCR2 was confined to astrocytes and increased dramatically within 24 h in both mouse types. Contrarily, CCR5 expression remained constitutively low and was mainly localized to microglia. These results show that after CHI, chemokines and their receptors are regulated differentially and with independent kinetics.

The Chemokine Fractalkine in Patients With Severe Traumatic Brain Injury and a Mouse Model of Closed Head Injury

The potential role of the chemokine Fractalkine (CX3CL1) in the pathophysiology of traumatic brain injury (TBI) was investigated in patients with head trauma and in mice after experimental cortical contusion. In control individuals, soluble (s)Fractalkine was present at low concentrations in cerebrospinal fluid (CSF) (12.6 to 57.3 pg/mL) but at much higher levels in serum (21,288 to 74,548 pg/mL). Elevation of sFractalkine in CSF of TBI patients was observed during the whole study period (means: 29.92 to 535.33 pg/mL), whereas serum levels remained within normal ranges (means: 3,100 to 59,159 pg/mL). Based on these differences, a possible passage of sFractalkine from blood to CSF was supported by the strong correlation between blood–brain barrier dysfunction (according to the CSF-/serum-albumin quotient) and sFractalkine concentrations in CSF (R = 0.706; P < 0.01). In the brain of mice subjected to closed head injury, neither Fractalkine protein nor mRNA were found to be augmented; however, Fractalkine receptor (CX3CR1) mRNA steadily increased peaking at 1 week postinjury (P < 0.05, one-way analysis of variance). This possibly implies the receptor to be the key factor determining the action of constitutively expressed Fractalkine. Altogether, these data suggest that the Fractalkine-CX3CR1 protein system may be involved in the inflammatory response to TBI, particularly for the accumulation of leukocytes in the injured parenchyma.

Minimally Invasive Vertebral Replacement with Cages in Thoracic and Lumbar Spine

AbstractPatients and Methods: Anterior reconstruction of the thoracic and lumbar spine was performed using Synex™-cages for vertebral body replacement implanted via open but minimally invasive access in 57 patients with trauma (n = 48), metastasis (n = 6), pseudarthrosis (n = 2), and spondylodiscitis (n = 1). Results: No case had to be changed into an open procedure. The upper thoracic spine was approached by a right-sided (n = 10), the thoracolumbar junction by a left-sided (n = 37) mini-thoracotomy, and the lumbar spine by a left-sided mini-retroperitoneal approach (n = 10). The overall mean operating time was 150 min (range 40–325 min) but varied depending on the spine pathology and the magnitude of the intervention to the anterior part of the spine. There were neither visceral/vascular complications nor other intra- or postoperative complications related to the minimal access in particular. No intercostal neuralgias, no post-thoracotomy pain syndromes and no superficial or deep wound infections occurred. One patient with metastatic destruction of the vertebra died intraoperatively due to a thromboembolic complication caused by his underlying disease. Two cases of pseudo-obstruction were treated conservatively. Conclusion: In this study, we describe the use of a new vertebral body replacement for reconstruction of the thoracic and lumbar spine which had been implanted by minimal-access technology.

Die transgene intrazerebrale Expression des Komplement-Inhibitors sCrry vermittelt eine Verbesserung der Blut-Hirn-Schranken-Funktion im experimentellen Schädel-Hirn-Trauma der Maus

The posttraumatic disruption of the blood-brain barrier function contributes to neuropathological sequelae of traumatic brain injury, leading to the development of cerebral edema, increased intracranial pressure, and adverse outcome. Clinical data have suggested a role of intracerebral complement activation after traumatic brain injury in mediating posttraumatic blood-brain barrier damage. In this study, we demonstrate that transgenic mice with astrocyte-targeted expression of the soluble complement inhibitor sCrry have a significantly improved blood-brain barrier function after closed head injury compared to wild-type C57BL/6 littermates, both on a quantitative (intracerebral Evans blue extravasation) and on a qualitative basis (albumin deposition in the subarachnoid space). These data provide the rationale for new pharmacological strategies aimed at reducing the extent of secondary brain damage in neurotrauma.