Critical role of oxygen radicals in the initiation of hepatic depression after trauma hemorrhage.
BACKGROUND
Although depression in hepatocellular function occurs early after trauma and severe hemorrhage and persists despite fluid resuscitation, it remains unknown whether reactive oxygen species (ROS) play any role in the initiation of hepatocellular depression and damage under those conditions. We hypothesized that administration of a ROS scavenger at the beginning of resuscitation will attenuate organ injury after severe shock.


METHODS
Male Sprague-Dawley rats (275-325 g) underwent laparotomy (i.e., induction of soft tissue trauma) and were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer's lactate. The animals were then resuscitated with four times the volume of maximal bleed-out with RL over 60 minutes. The ROS scavenger 2-mercaptopropionyl glycine (30 mg/kg) or vehicle was administered intravenously as a bolus at the beginning of resuscitation. At 2 hours after the completion of crystalloid resuscitation or the equivalent interval after sham-operation, cardiac index was measured by a dye dilution technique. Hepatocellular function, i.e., the maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the active transport (Km), was determined using an in vivo hemoreflectometer. Serum levels of tumor necrosis factor (TNF)-alpha and alanine aminotransferase were determined with ELISA and colorimetrically, respectively.


RESULTS
The results indicate that at 2 hours after trauma hemorrhage and resuscitation, cardiac index and hepatocellular function were markedly depressed with concomitantly increased serum levels of TNF-alpha and alanine aminotransferase (p < 0.05). Administration of 2-mercaptopropionyl glycine, however, restored the depressed cardiac and hepatic function and markedly attenuated liver enzyme release and serum levels of TNF-alpha (p < 0.05).


CONCLUSIONS
Our data suggest that ROS play a role in producing the depression in organ functions after severe hemorrhagic shock. Thus, adjuncts that attenuate the detrimental effects of ROS may be useful for improving the depressed cardiac and hepatocellular functions after trauma hemorrhage and resuscitation.
Jarrar
D
D
Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, USA.
Wang
P
P
Cioffi
W G
WG
Bland
K I
KI
Chaudry
I H
IH
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002302:Cardiac Output; D004195:Disease Models, Animal; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D007208:Indocyanine Green / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D017093:Liver Failure / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D008111:Liver Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012151:Resuscitation / Q000379:methods; D012771:Shock, Hemorrhagic / Q000150:complications*; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000975:Antioxidants; D016166:Free Radical Scavengers; C110658:N-(2-mercaptoproprionyl)-glycine; D017382:Reactive Oxygen Species; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase; D007208:Indocyanine Green; D005998:Glycine