The Acute Inflammatory Response in Trauma / Hemorrhage and Traumatic Brain Injury: Current State and Emerging Prospects

Abstract

Traumatic injury/hemorrhagic shock (T/HS) elicits an acute inflammatory response that may result in death. Inflammation describes a coordinated series of molecular, cellular, tissue, organ, and systemic responses that drive the pathology of various diseases including T/HS and traumatic brain injury (TBI). Inflammation is a finely tuned, dynamic, highly-regulated process that is not inherently detrimental, but rather required for immune surveillance, optimal post-injury tissue repair, and regeneration. The inflammatory response is driven by cytokines and chemokines and is partially propagated by damaged tissue-derived products (Damage-associated Molecular Patterns; DAMP's). DAMPs perpetuate inflammation through the release of pro-inflammatory cytokines, but may also inhibit anti-inflammatory cytokines. Various animal models of T/HS in mice, rats, pigs, dogs, and non-human primates have been utilized in an attempt to move from bench to bedside. Novel approaches, including those from the field of systems biology, may yield therapeutic breakthroughs in T/HS and TBI in the near future.

Administration of COG1410 Reduces Axonal Amyloid Precursor Protein Immunoreactivity and Microglial Activation after Controlled Cortical Impact in Mice

“…Inflammatory responses may contribute to secondary injury cascades that promote continued cellular destruction, but it also could play a key role in repair and regeneration of the injury (Kelley et al, 2007;Namas et al, 2009;Shein et al, 2008). It is not known whether persistent microglial activation is beneficial, neutral, or harmful on the whole.…”

“…One hypothesis is that microglia have a harmful effect on pericontusional axonal injury, and that reduction in the microglial response is the proximal mechanism by which COG1410 affects TAI. Additional interventions targeting microglia will be necessary to directly address this hypothesis (Elliott et al, 2011;Grathwohl et al, 2009;Namas et al, 2009). By analogy, minocycline, which may also inhibit microglial activation, has been shown to improve outcomes in other experimental injury models (Kim and Suh 2009).…”

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

“…76 Microglial cells contribute to neuroinflammation in response to DAMPS by secreting proinflammatory cytokines, such as interleukin (IL)-1 and tumor necrosis factor alpha (TNF-a), which amplify the inflammatory response by initiating the production of other cytokines and promoting microglial proliferation and activation of astrocytes. 70 The early phase of TBI-induced reactive gliosis has been reported to begin in with predominant microglia activation that peaks within 1 week, 28,[77][78][79][80][81][82] but continues for several weeks and overlaps later with persistent astrocytic activation. 28,82,83 Our IHC results support this time course, indicating injury-induced astrogliosis in the insula and amygdala at 6 months postinjury, but less activation of microglia (only significant in the amygdala), suggesting that microglial activation may precede astrocytic activation and modulate the onset and maintenance of astrogliosis.…”

“…21,[71][72][73] Damage-associated molecular patterns (DAMPs) play an important role in the propagation of the proinflammatory cascade of innate immunity, promoting the release of cytokines and other inflammatory mediators. 70,74 DAMPs initiate the innate immune response through the activation of APCs, which up-regulate costimulatory and major histocompatibility complex molecules. 21,71,75 APCs respond to endogenous signals through Toll-like receptors (TLRs), which recognize a variety of DAMPs and act as pattern recognition receptors for endogenous molecules.…”

“…[9][10][11][12] Chronic post-traumatic neuroinflammation suggests the presence of a self-perpetuating positive feedback loop, possibly involving reactivation and further promotion of inflammatory mediators after injury in an inflammation-damage-inflammation cycle. 70 Stressed, damaged, and injured cells release endogenous danger signals, which trigger local inflammatory responses needed for tissue repair and regeneration. 21,[71][72][73] Damage-associated molecular patterns (DAMPs) play an important role in the propagation of the proinflammatory cascade of innate immunity, promoting the release of cytokines and other inflammatory mediators.…”