Host responses to concurrent combined injuries in non-human primates.

BACKGROUND: Multi-organ failure (MOF) following trauma remains a significant cause of morbidity and mortality related to a poorly understood abnormal inflammatory response. We characterized the inflammatory response in a non-human primate soft tissue injury and closed abdomen hemorrhage and sepsis model developed to assess realistic injury patterns and induce MOF. METHODS: Adult male Mauritan Cynomolgus Macaques underwent laparoscopy to create a cecal perforation and non-anatomic liver resection along with a full-thickness flank soft tissue injury. Treatment consisted of a pre-hospital phase followed by a hospital phase after 120 minutes. Blood counts, chemistries, and cytokines/chemokines were measured throughout the study. Lung tissue inflammation/apoptosis was confirmed by mRNA quantitative real-time PCR (qPCR), H&E, myeloperoxidase (MPO) and TUNEL staining was performed comparing age-matched uninjured controls to experimental animals. RESULTS: Twenty-one animals underwent the protocol. Mean percent hepatectomy was 64.4 ± 5.6; percent blood loss was 69.0 ± 12.1. Clinical evidence of end-organ damage was reflected by a significant elevation in creatinine (1.1 ± 0.03 vs. 1.9 ± 0.4, p=0.026). Significant increases in systemic levels of IL-10, IL-1ra, IL-6, G-CSF, and MCP-1 occurred (11-2986-fold) by 240 minutes. Excessive pulmonary inflammation was evidenced by alveolar edema, congestion, and wall thickening (H&E staining). Concordantly, amplified accumulation of MPO leukocytes and significant pulmonary inflammation and pneumocyte apoptosis (TUNEL) was confirmed using qRT-PCR. CONCLUSION: We created a clinically relevant large animal multi-trauma model using laparoscopy that resulted in a significant systemic inflammatory response and MOF. With this model, we anticipate studying systemic inflammation and testing innovative therapeutic options.

An Evolving Uncontrolled Hemorrhage Model Using Cynomolgus Macaques.

BACKGROUND: Trauma-induced hemorrhagic shock produces hemodynamic changes that often result in a systemic inflammatory response that can lead to multiple organ failure and death. In this prospective study, the pathophysiology of a nonhuman primate uncontrolled hemorrhagic shock model is evaluated with the goal of creating an acute systemic inflammatory syndrome response and a reproducible hemorrhage. METHODS: Nonhuman primates were divided into 2 groups. A laparoscopic left hepatectomy was performed in groups A and B, 60% and 80%, respectively, resulting in uncontrolled hemorrhage. Resuscitation during the prehospital phase lasted 120 min and included a 0.9% saline bolus at 20 mL/kg. The hospital phase involved active warming, laparotomy, hepatorrhaphy for hemostasis, and transfusion of packed red blood cells (10 mL/kg). The animals were recovered and observed over a 14-day survival period with subsequent necropsy for histopathology. RESULTS: Baseline demographics and clinical parameters of the two groups were similar. Group A (n = 7) underwent a 57.7% ± 2.4% left hepatectomy with a 33.9% ± 4.0% blood loss and 57% survival. Group B (n = 4) underwent an 80.0% ± 6.0% left hepatectomy with 56.0% ± 3.2% blood loss and 75% survival. Group B had significantly lower hematocrit (P < 0.05) for all postinjury time points. Group A had significantly elevated creatinine on postoperative day 1. Nonsurvivors succumbed to an early death, averaging 36 h from the injury. Histopathologic evaluation of nonsurvivors demonstrated kidney tubular degeneration. CONCLUSIONS: Nonhuman primates displayed the expected physiologic response to hemorrhagic shock due to liver trauma as well as systemic inflammatory response syndrome with resultant multiple organ dysfunction syndrome and either early death or subsequent recovery. Our next step is to establish a clinically applicable nonhuman primate polytrauma model, which reproduces the prolonged maladaptive immunologic reactivity and end-organ dysfunction consistent with multiple organ failure found in the critically injured patient.

Modeling acute traumatic injury.

Acute traumatic injury is a complex disease that has remained a leading cause of death, which affects all ages in our society. Direct mechanical insult to tissues may result in physiological and immunologic disturbances brought about by blood loss, coagulopathy, as well as ischemia and reperfusion insults. This inappropriate response leads to an abnormal release of endogenous mediators of inflammation that synergistically contribute to the incidence of morbidity and mortality. This aberrant activation and suppression of the immune system follows a bimodal pattern, wherein activation of the innate immune responses is followed by an anti-inflammatory response with suppression of the adaptive immunity, which can subsequently lead secondary insults and multiple organ dysfunction. Traumatic injury rodent and swine models have been used to describe many of the underlying pathologic mechanisms, which have led to an improved understanding of the morbidity and mortality associated with critically ill trauma patients. The enigmatic immunopathology of the human immunologic response after severe trauma, however, has never more been apparent and there grows a need for a clinically relevant animal model, which mimics this immune physiology to enhance the care of the most severely injured. This has necessitated preclinical studies in a more closely related model system, the nonhuman primate. In this review article, we summarize animal models of trauma that have provided insight into the clinical response and understanding of cellular mechanisms involved in the onset and progression of ischemia-reperfusion injury as well as describe future treatment options using immunomodulation-based strategies.