The Role of Neuroinflammation in Traumatic Brain Injury

Abstract

In industrialized countries, traumatic brain injury (TBI) still represents the leading cause of death and persisting neurologic impairment among young individuals < 45 years of age. Patients who survive the initial injury are susceptible to sustaining secondary cerebral insults which are initiated by the release of neurotoxic and inflammatory endogenous mediators by resident cells of the central nervous system (CNS). The presence of hypoxia and hypotension in the early resuscitative period further aggravates the inflammatory response due to ischemia/reperfusion-mediated injuries. These are induced by the intrathecal generation of free radicals and activation of the complement cascade. Posttraumatic neuroinflammation is further exacerbated by the subsequent intracranial recruitment of blood-derived immunocompetent cells, leading to secondary cerebral edema and increased intracranial pressure. The profound endogenous neuroinflammatory response after TBI, which is phylogenetically aimed at defending the CNS from invading pathogens and repairing lesioned tissue, is, in large part, responsible for the development of secondary brain damage and adverse outcome. However, aside from these deleterious effects, posttraumatic inflammation mediates neuroreparative mechanisms after TBI as well. This "dual effect" of neuroinflammation has been the focus of extensive experimental and clinical research in the past years and has led to an expanded basic knowledge on the cellular and molecular mechanisms which regulate the intracranial inflammatory response after trauma. The present article provides an up-to-date overview on the pathophysiological mechanisms of neuroinflammation after TBI. New potential therapeutic strategies for reducing the extent of secondary brain damage after neurotrauma are discussed.

Analysis of key genes and modules during the courses of traumatic brain injury with microarray technology

“…It is involved in inflammation (Qin et al, 1998;Bing et al, 2006) and thus plays a role in the pathogenesis of brain injury and neurodegenerative disorders (Whitney et al, 2009). It has been found to be upregulated in TBI (Schmidt et al, 2004) and this was confirmed in the present study. Galasso et al (1998) reported that excitotoxic brain injury stimulates expression of the chemokine receptor CCR5 in neonatal rats.…”

Blast-induced moderate neurotrauma (BINT) elicits early complement activation and tumor necrosis factor alpha (TNFα) release in a rat brain

“…Severe secondary insults in TBI were paralleled by more pronounced complement activation, particularly by the end product C5b-9 [13]. These secondary injuries include the recruitment of inflammatory cells into the intrathecal compartment, the induction of BBB dysfunction by the anaphylatoxins C3a and C5a, the induction of neuronal apoptosis through the C5a receptor (C5aR) expressed on neurons, and homologous cell lysis mediated by complement activation through the membrane attack complex (MAC/C5b-9) [14]. A recent study from our group has shown that complement activation is associated with hypoxia-induced disruption of neuronal network, loss of dendritic spine, and neuronal apoptosis [15].…”

Screening for the Formation of Reactive Oxygen Species and of NO in Muscle Tissue and Remote Organs upon Mechanical Trauma to the Mouse Hind Limb

“…Very early posttraumatic ROS generation, as in our experiments, so far has only been re- ported from CNS trauma experiments, which also do not clarify the defi nite cellular source of the generated reactive species [6,10,11] . In the literature, the consequences of an enhanced ROS formation following acute cell injury of different origin are assumed to constitute the basis of an exacerbated destruction of cells and tissues resulting in disease and organ failure [28,31] . The generation of oxidants as a likely harmful result of blunt muscle trauma in our experiments thus correlates well with the data on ROS generation in CNS trauma, a fi nding that is further supported by the local protection that was achieved by antioxidant treatment in experimental impact injury to the rat hind limb and brain [32,33] .…”