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.

Keywords: Hemorrhagic Shock; Inflammation; Systems Biology; Trauma; Traumatic Brain Injury.

Figure 1

The ‘one-hit’ and ‘two-hit’ paradigm of traumatic injury. ‘One hit’ represents the initial, massive tissue injury and shock and SIRS along with remote organ injury. The ‘second hit’ refers to the less intense SIRS that normally resolves but leaves the patient vulnerable to a secondary inflammatory hit that can reactivate the SIRS and precipitate late MODS.

Figure 2

The inflammatory response to tissue injury. Traumatic injury signals various cell types to produce cytokines, chemokines, and DAMPs. In turn, DAMPs re-activate and further propagate the production of inflammatory mediators, setting in motion a positive feedback loop of inflammation→damage→inflammation.

Figure 3

The spectrum of cytokines, chemokines, and DAMPs in T/HS and TBI. The inflammatory response generated in response to T/HS or TBI can be assessed by measuring a panoply of cytokines, chemokines, DAMPs, and ultimate markers of endorgan damage. Some of these biomarkers may also be candidates for therapeutic intervention.

Figure 4

A vision for the future of drug design for T/HS and TBI. The future of rational drug design for T/HS and TBI may involve the use of in silico (computer simulated) that would be based on a mechanistic understanding of the inflammatory response as well as pharmacokinetic and pharmacodynamic principles and used to determine the optimal properties, dosage, timing, and inclusion/exclusion criteria for a given drug candidate's clinical trial. Key aspects of these simulations would be tested iteratively in cell culture experiments and pre-clinical animal models, streamlining the process (and reducing the time and cost) of clinical trial design and implementation.