Assessment of the Immediate, Short-, and Long-Term Deleterious Consequences of Polytraumatic Injury in a Critical Care Non-Human Primate Model

Background: The long-term treatment of military Warfighters who sustain severe battlefield blast-related injuries involving severe hemorrhage is currently one of the major challenges for military healthcare providers. Survival from these injuries has largely been due to improvements in first-responder care, evacuation times, and resuscitation practices. Unfortunately, many of these patients have succumbed to their injuries several days later secondary to multi-organ failure (MOF), which remains a significant cause of morbidity and mortality in trauma. The pathophysiology behind MOF is related to a maladaptive systemic inflammatory response syndrome (SIRS) triggered by the release of excessive inflammatory cytokines. Currently, the underlying mechanism for immune dysregulation is poorly understood, and there are no existing preclinical models that accurately reflect the clinical scenarios that play out in severely injured patients prone to development of SIRS. Further, outside of supportive care, there are limited existing strategies for preventing or treating SIRS following complex combat trauma. Moreover, this threatening immunological phenomenon has not been systematically studied as a potential important contributing risk factor for post-injury health complications. We believe that complex blast-related injuries involving severe hemorrhage result in a state of acquired immune dysfunction that persists long after injury and contributes to the development of a number of downstream chronic health problems.Hypothesis: We hypothesize that the exaggerated innate and adaptive immune responses (activated T cells) that drives SIRS/ multiple organ dysfunction syndrome, and perpetuate soluble proinflammatory factor production and tissue damage following acute polytraumatic injury can be rapidly and significantly dampened/modulated using candidate drugs and/or stem-cell based therapy noted to possess the ability to impart profound immunmodulatory effects both in vitro and in vivo. Therapeutic testing and assessment of agents for clinical efficacy is dependent on the development of a clinical relevant model that include those critical injury patterns and follow-on clinical support required for induction/onset as well as the clinical management of the immediate, short- and long-term deleterious consequences of polytraumatic injury in a non-human critical care primate model.Specific Aims: In this proposal (Phase I), we will refine our existing the existing non-human primate poly-trauma model focusing on long-term survival and supportive care endpoints. Specifically, we will (1) develop a more clinically relevant model with the institution of a 24- to 72-hour ventilator support component (or longer if necessary as dictated by the animals physiology), appropriate ventilator weaning protocol, and full-time intensive care support to allow for a more thorough study of severe trauma; (2) measure serum cytokines/chemokines, other systemic inflammatory mediators/danger signaling molecules, and coagulation parameters to identify therapeutic targets to mitigate the associated MOF; (3) assess the effects of polytraumatic injury on cutaneous wound healing; (4) measure the incidence and activation status of circulating innate and adaptive immune cell populations; and (5) evaluate and determine the long-term end-organ effects, specifically pulmonary function, after trauma in order to more fully understand the long-term sequela of polytrauma.Experimental Design: Using our established clinically relevant non-human polytrauma model, we will add a post-operative course simulating an intensive care unit environment, which will allow for better care of ensuing organ failure. This will include ventilatory support for the resultant lung injury as we have found the majority of our mortality due to respiratory distress/failure during which we have had the inability to provide the appropriate, realistic respiratory support. We will examine the immediate, short-, and long-term deleterious consequences of polytraumatic injury.Military Benefit: Trauma is the leading cause of preventable death. Both blunt and penetrating trauma may result in massive tissue damage, hemorrhage, and concomitant shock physiology. This is particularly true with regard to common battlefield injuries. Multiple injuries and hemorrhage can induce a maladaptive immune response leading to significant morbidity and mortality independent of the traumatic injuries. The impact of a chronic inflammatory state and its association with post-injury complications has not been elucidated in a clinically relevant model of polytraumatic injury. By characterizing these pathways and identifying potentially modifiable factors, ultimately we may be able to mitigate the resultant downstream health issues.Innovation: The current proposal will fill existing and emerging gaps in the Combat Casualty Care Program to improve treatment for Service members injured in combat. Understanding and defining the physiologic and immunologic responses after polytraumatic injury in a stringent and clinical relevant animal model will provide insight for the clinical management and for the development of innovative therapeutic interventions/strategies designed to improve the clinical outcome after combat-related trauma.