Development and Characterization of a Rat Model of Blast Polytrauma and Hemorrhagic Shock for Evaluating Innate Immunotherapies During Prolonged Damage Control Resuscitation.

Abstract

<h4>Background</h4>A major challenge in developing effective immunological damage-control therapies for traumatic hemorrhage (TH) is the lack of animal models that accurately reproduce the immune and pathophysiological responses observed in humans. In this study, we established a clinically relevant rat model that combines blast injury with hemorrhagic shock in a simulated prolonged damage control resuscitation environment.<h4>Methods</h4>Male Sprague Dawley rats were anesthetized and subjected to moderate blast overpressure, followed by controlled hemorrhage equivalent to 40% of the estimated total blood volume. Animals then received hypotensive resuscitation with Plasma-Lyte A at twice the shed blood volume. Plasma-Lyte A was used in our study to correct hypovolemia and electrolyte imbalances, thereby helping to standardize the traumatic hemorrhage model.<h4>Results</h4>Four of six rats in the blast-plus-hemorrhage (B + H) group survived the 25 h observation period. During resuscitation, mean arterial pressure remained markedly below baseline for at least 4 h. The B + H insult triggered a rapid innate immune response, characterized by elevated circulating HMGB1, terminal complement activation, and increased myeloperoxidase levels. Complement deposition (C4d, C5a, and C5b-9) was evident in lung tissue, accompanied by multi-organ histopathological injury, including pronounced inflammatory cell infiltration, hemorrhage, and cellular degeneration, apoptosis, or necrosis. Metabolic disturbances, including acidosis, hyperkalemia, and dilutional anemia, were also observed.<h4>Conclusions</h4>Overall, this model reproduced key features of inflammation-driven multi-organ dysfunction syndrome seen in human polytrauma, supporting its utility for studying TH-related immunopathology and therapeutic interventions during prolonged damage control resuscitation.