Activation of NF-κB Mediates Astrocyte Swelling and Brain Edema in Traumatic Brain Injury

Abstract

Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). While astrocyte swelling (cytotoxic edema) represents a major component of the brain edema in the early phase of TBI, its mechanisms are unclear. One factor known to be activated by trauma is nuclear factor-jB (NF-jB). Because this factor has been implicated in the mechanism of cell swelling/brain edema in other neurological conditions, we examined whether NF-jB might also be involved in the mediation of post-traumatic astrocyte swelling/brain edema. Here we show an increase in NF-jB activation in cultured astrocytes at 1 and 3 h after trauma (fluid percussion injury, FPI), and that BAY 11-7082, an inhibitor of NF-jB, significantly blocked the trauma-induced astrocyte swelling. Increased activities of nicotinamide adenine dinucleotide phosphate-oxidase and the Na + , K + , 2Cl -cotransporter were also observed in cultured astrocytes after trauma, and BAY 11-7082 reduced these effects. We also examined the role of NF-jB in the mechanism of cell swelling by using astrocyte cultures derived from transgenic (Tg) mice with a functional inactivation of astrocytic NF-jB. Exposure of cultured astrocytes from wild-type mice to in vitro trauma (3 h) caused a significant increase in cell swelling. By contrast, traumatized astrocyte cultures derived from NF-jB Tg mice showed no swelling. We also found increased astrocytic NF-jB activation and brain water content in rats after FPI, while BAY 11-7082 significantly reduced such effects. Our findings strongly suggest that activation of astrocytic NF-jB represents a key element in the process by which cytotoxic brain edema occurs after TBI.

Neuronal Cell Death Induced by Mechanical Percussion Trauma in Cultured Neurons is not Preceded by Alterations in Glucose, Lactate and Glutamine Metabolism

“…Additionally, we previously documented that following in vitro mechanical trauma to cultured astrocytes, changes in various intracellular signaling systems, as well as in cell swelling occurred [27–30], and that such changes correlated well with in vivo findings [41, 32]. Altogether, these findings strongly suggest that our in vitro cell injury system is indeed a highly suitable system for investigating mechanisms of trauma-induced injury to neural cells.…”

“…The in vitro system has the unique advantage of clearly delineating mechanisms and analyzing the responses to trauma in different cell types (neurons and astrocytes). We have found that this system reliably produces consistent degrees of traumatic injury [28–30]. …”

“…Additionally, many of the findings occurring in TBI in vivo, including neuronal death in the early stages following trauma (24 h) [31–33]; changes in neuronal proteins (i.e., altered synaptic proteins including PSD95, NMDA-R, synaptotagmin, synaptophysin and NADPH oxidase activity [34–38]; altered neuronal signaling systems (MAPKs activity and changes in transcription factor levels) [39, 30]; and characteristic morphologic changes [40] are also observed in these cultures following mechanical trauma. Additionally, we previously documented that following in vitro mechanical trauma to cultured astrocytes, changes in various intracellular signaling systems, as well as in cell swelling occurred [27–30], and that such changes correlated well with in vivo findings [41, 32].…”

“…Briefly, the injury chamber was coupled to the fluid percussion injury device with non-distensible Tygon tubing, and the piston was percussed by the weighted pendulum at varying angles of incidence [27–30]. Five atmospheres of pressure were administered twice for a 25-milliseconds duration each.…”

Astrocyte roles in traumatic brain injury

“…Pattern recognition receptor-mediated NFκB signaling in astrocytes also results in cell swelling implicated in cytotoxic edema, a major pathophysiologic mechanism underlying the harmful increase in intracranial pressure following TBI (Jayakumar et al, 2014). Correspondingly, HMGB1 release following TBI-induced tissue damage can signal to microglia, inducing secretion of IL-6 that signals reactive astrocytes to upregulate the AQP4 water channel involved in astroglial water uptake (Laird et al, 2014).…”