Introduction: Severe traumatic brain injury (TBI) is a major cause of death and disability. There is a growing body of research to indicating that severe TBI patients are at acute risk of severe infection while in the intensive care unit (ICU). This increased risk of infection correlates with an acute decline in systemic immune function, sometimes referred to as immunoparalysis. There is limited understanding as to why immunoparalysis occurs following brain injury. We have developed an animal model of brain injury in rats that recapitulates this phenomenon for preclinical study.

Methods: Adult Sprague-Dawley rats were used for all experiments. A moderately severe brain injury at the prefrontal cortex was induced using a controlled cortical impact model. Blood draws were performed before injury and on days 1 and 3 following injury. Immune response was determined by assessment of tumor necrosis factor alpha (TNFa) production capacity. Neurological injury from the TBI was confirmed using a Barnes maze. Gross histology of the lesion was examined using luxol fast blue and hematoxylin and eosin.

Results: A significant, 67% decrease in TNFa production capacity following induced TBI was noted at post-injury day 1, as compared with sham-surgery animals. In the injured animals, this decrease in immune response normalized by post-injury day 3. The induced injury led to significant impairments in spatial memory and learning. The induced injury also produced a lesion cavity still notable at 4 weeks post-injury.

Conclusions: The data presented demonstrate that induced TBI led to a significant decline in immune function immediately following the injury. These findings mirror observations seen in TBI patients. The creation of an animal model of post-TBI immunoparalysis may allow for improved understanding of the mechanism, improved diagnostic tools for its detection, and more specific, directed therapy.

Patient Care: A decline in immune function following injury may make patients more susceptible to nosocomial infections. This research may identify why immunoparalysis occurs following injury, allowing for the development of specific agents to prevent immunoparalysis following injury.

Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of immunoparalysis following traumatic brain injury, 2) Discuss, in small groups, the possible consequences and advantages of immunoparalysis following traumatic brain injury 3) Identify possible methods for preventing/treating immunoparalysis following traumatic brain injury.

References: 1. Muszynski JA, Nofziger R, Greathouse K, Nateri J, Hanson-Huber L, Steele L, Nicol K, Groner JI, Besner GE, Raffel C, Geyer S, El-Assal O, Hall MW. Innate immune function predicts the development of nosocomial infection in critically injured children. Shock. 2014 Oct;42(4):313-21. 2. Fabregas N, Torres A. Pulmonary infection in the brain injured patient. Minerva Anestesiol 2002, 68:285-290. 3. Ackermann M, Reuter M, Flohé S, Bahrami S, Redl H, Schade FU. Cytokine synthesis in the liver of endotoxin-tolerant and normal rats during hemorrhagic shock. J Endotoxin Res. 2001;7(2):105-12. 4. Romine J, Gao X, Chen J. Controlled cortical impact model for traumatic brain injury. J Vis Exp. 2014; (90). 5. Geddes RI, Sribnick EA, Sayeed I, Stein DG. Progesterone treatment shows benefit in a pediatric model of moderate to severe bilateral brain injury. PLoS One. 2014 Jan 28;9(1):e87252. 6. Barnes, CA. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol. 1979;93(1):74-104. 7. van Leeuwen N, Lingsma HF, Perel P, Lecky F, Roozenbeek B, Lu J,et al. Prognostic value of major extracranial injury in traumatic brain injury: an individual patient data meta-analysis in 39,274 patients. Neurosurgery. 2012;70(4):811-8. 8. Shein SL, Shellington DK, Exo JL, Jackson TC, Wisniewski SR, Jackson EK, Vagni VA, Bayir H, Clark RS, Dixon CE, Janesko-Feldman KL, Kochanek PM. Hemorrhagic shock shifts the serum cytokine profile from pro- to anti-inflammatory after experimental traumatic brain injury in mice. J Neurotrauma. 2014;31(16):1386-95. 9. Fülöp A, Turóczi Z, Garbaisz D, Harsányi L, Szijártó A. Experimental models of hemorrhagic shock: a review. Eur Surg Res. 2013;50(2):57-70. 10. Thakkar RK, Chung CS, Chen Y, Monaghan SF, Lomas-Neira J, Heffernan DS, Cioffi WG, Ayala A. Local Tissue Expression of the Cell Death Ligand, FasL, Plays a Central Role in the Development of Extra-Pulmonary Acute Lung Injury. Shock. 2011 Aug; 36(2) PMID21451443 11. Monaghan SF, Thakkar RK, Chung CS, Xin H, Lomas-Neira J, Heffernan DS, Cioffi WG, Ayala A. Mechanisms of Indirect Acute Lung Injury: A Novel Role for the Co-Inhibitory Receptor, Programmed Death-1, (PD-1). Annals of Surgery. 2012 PMID21997806 12. Lomas-Neira J, Venet F, Chung CS, Thakkar RK, Heffernan DS, Ayala A. Neutrophil-Endothelial Interactions Mediate Angiopoietin-2 associated Pulmonary Endothelial Cell Dysfunction in Indirect ALI in Mice. American Journal of Respiratory Cell and Molecular Biology. 2014 Jan;50(1):193-200 PMID23980650 13. Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous system injury-induced immune deficiency syndrome. Nat Rev Neurosci. 2005 Oct;6(10):775-86. 14. Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K, Pavlov VA, Gallowitsch-Puerta M, Ashok M, Czura CJ, Foxwell B, Tracey KJ, Ulloa L. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med. 2006;203(7):1623-8. 15. Rosas-Ballina M, Olofsson PS, Ochani M, Valdés-Ferrer SI, Levine YA, Reardon C, Tusche MW, Pavlov VA, Andersson U, Chavan S, Mak TW, Tracey KJ. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 2011;334(6052):98-101.