Plasma-Derived C1 Esterase Inhibitor Treatment to Switch the Injury Phenotype to an Organ-Protective Phenotype after Traumatic Hemorrhage in Rats

Background: Hemorrhage is a major preventable cause of death in patients with trauma. Dysregulated complement activation constitutes part of the "second hit" of trauma, resulting in end-organ dysfunction. This study aimed to evaluate the effect of plasma-derived C1 inhibitor (pdC1-INH) on multi-organ damage in a rat model of combined blast injury and volume-controlled hemorrhage. Methods: Anesthetized rats underwent moderate blast overpressure and severe bleeding (52%). The injured animals were randomized to two groups: 1) Injury + Placebo (n=10), and 2) Injury + pdC1-INH (200U/kg, i.v, n=10). After 30 min of the shock phase, all the animals received 2x the shed blood volume of Plasma-Lyte A and were monitored up to 24 hours after the shock. Results: Pharmacokinetic measurement revealed Cmax (2.69 ± 0.2U/ml) by 45min, clearance (1.29 ± 0.75 ml/min), volume distribution (14.2 ± 0.45 ml), and half-life (8.27 ± 1.96h). The pharmacodynamic assessment showed that pdC1-INH treatment significantly inhibited the terminal complement activity by 75% at 11h and remained at 50% inhibition until the end of the experiment. Administration of pdC1-INH significantly alleviated tissue inflammation and organ damage in the brain and liver but not in the lung tissue compared to the placebo. However, there was no significant difference in mortality between pdC1-INHtreated and placebo-treated animals. Conclusion: pdC1-INH switched the injury phenotype to an organ-protective phenotype after blast injury and hemorrhage by mitigating tissue inflammation. The utilization of pdC1-INH in prehospital settings may lead to a significant reduction in morbidity and mortality of military and civilian trauma patients.