On the role of complement activation following traumatic brain injury
Abstract: Traumatic brain injury (TBI) is one of the leading causes of early death and disability among young people in the industrial world. The final clinical outcome in terms of morbidity/mortality is not only related to the "primary brain injury", but also seems to be dependent on the potential development of so called "secondary injuries", that may occur in the brain the days after the initial impact. Several biochemical mechanisms have been suggested to be involved in these secondary events, like release of free radicals, glutamate, proteases and nitric oxide. During recent years neuroinflammation has gained a growing interest as a mediator of such secondary injuries. One important immunological entity is the complement system, which when activated results in a cascade of events leading to increased vascular permeability, induction of cytokine production which further triggers the inflammatory response, facilitation of phagocytosis by chemotactical recruitment of macrophages and opsonization. The terminal pathway of the complement cascade results in formation of the membrane attack complex (MAC), a protein complex, with capacity to damage basically any target cell by creating pores in the cell membrane, which in turn allows intracellular influx of water and ions, e.g. calcium, that eventually may cause cell death. In this thesis we have shown that the complement cascade is activated in the border zone ("penumbra") of a brain contusion in the adult rat as well as in the human brain. Clusters of MAC, the cytolytic end-product of the complement cascade, were shown to accumulate at membrane surfaces of viable neurons located in the immediate vicinity to the primary brain injury and may thus contribute to additional damages, so called secondary brain injuries. Reactive microglia/macrophages seem to have a key role in complement activation by synthesis of at least complement factor C3. Resident microglial cells which in vivo are difficult to distinguish from peripherally derived monocytes/macrophages were shown in this thesis to contribute to the pool of reactive macrophages surrounding the lesion using an experimental blood/serum free brain slice model. The subsequent neuronal degeneration that follows TBI was found to be more severe in a rat strain that, based on its genetic features, presents a more pronounced neuroinflammatory response, including complement activation, supporting the hypothesis that this biological cascade is involved in the development of secondary brain injuries. Furthermore, in humans suffering from severe traumatic brain injuries, the occurrences of hypoxia, hypotension and other so called "secondary insults" is followed by higher levels of MAC as well as higher levels of the tissue damage marker S100B, in the cerebrospinal fluid, suggesting that secondary insults further enhance complement activation resulting in more and perhaps avoidable secondary injuries, provided that a thorough and systematic monitoring of these patients are undertaken as they are being treated in the neurointensive care unit. In summary, a traumatic brain injury causes a primary necrotic area surrounded by a "penumbra like" border zone where reactive microglial cells accumulate and transform into macrophages. These macrophages synthesize complement factor C3 and thus contribute to the activation of the complement cascade in the immediate vicinity to the contusion. The cytolytic end product of the complement system, MAC, may in turn induce secondary neuronal injuries by its membrane destructive effects, a process that is further enhanced by secondary insults. Future neuroprotective therapies might be based not only on avoiding secondary insults by careful monitoring, but also on specific regulatory compounds acting selectively on specific parts of the neuroinflammatory process, e.g. the terminal pathway of the complement systern.
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