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 (TNF alpha) production ex vivo. TNF alpha 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 TNF alpha 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.


CONCLUSIONS
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.
Majetschak
Matthias
M
Daughtry Department of Surgery, Divisions of Trauma and Surgical Critical Care, Ryder Trauma Center, University of Miami School of Medicine, Miami, Florida, USA. mmajetschak@med.miami.edu
Cohn
Stephen M
SM
Obertacke
Udo
U
Proctor
Kenneth G
KG
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D016903:Drug Monitoring / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005264:Femoral Fractures / Q000150:complications*; D005440:Fluid Therapy / Q000379:methods*; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D011897:Random Allocation; D012151:Resuscitation / Q000379:methods*; D012710:Serum Albumin, Bovine / Q000627:therapeutic use; D016037:Single-Blind Method; D013552:Swine; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D025801:Ubiquitin / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*
D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D012710:Serum Albumin, Bovine