Therapeutic potential of exogenous ubiquitin during resuscitation from severe trauma

Background: Recent studies suggest that extracellular ubiquitin could have a physiologic role in immunodepression in sepsis and trauma. The therapeutic potential of exogenous ubiquitin after trauma has not been examined. To fill this gap, we designed a series of experiments in a clinically relevant trauma model. Methods: Forty minutes after femur fractures and hemorrhage, swine received 1.3 mg of ubiquitin per kilogram or bovine serum albumin intravenously followed by fluid resuscitation to maintain systemic hemodynamics. Leukocyte function and the immunomodulatory capacity of serum were assessed measuring endotoxin-evoked tumor necrosis factor-alpha (TNFalpha) production ex vivo. TNF and ubiquitin were quantified with enzyme-linked immunosorbent assay. Results: Intravenous ubiquitin had no significant hemodynamic effect in normal animals. After injury, ubiquitin significantly reduced fluid requirements by at least 60% (p < 0.05). The injury was associated with transient immunodepression, as reflected by reduced endotoxin-evoked TNFalpha production by 40% to 50%. With ubiquitin, this response remained depressed for 100 to 160 minutes (p < 0.05), but fully recovered to baseline with albumin. Conclusion: Ubiquitin is apparently safe and effective for reducing fluid requirements as a measure of diffuse capillary leak. This immunomodulatory property suggests a new therapeutic approach after injury in particular, and for infectious and noninfectious inflammation in general.