Oxothiazolidine carboxylate provides protection against hepatocellular injury seen after porta hepatis occlusion (Pringle maneuver) under hypovolemic conditions.
ABSTRACT The sensitivity of liver to warm ischemia has always been a concern for surgeons. To monitor the ischemia and/or reperfusion injury after the Pringle maneuver (occlusion of porta hepatis) in livers subjected to hemorrhage, blood pressure, blood pH, base deficit (BE), serum alanine aminotransferase (ALT), serum and liver malondialdehyde (MDA), and liver glutathione (GSH) levels were measured. MDA is a by-product of oxidant induced lipid peroxidation, and GSH is an endogenous antioxidant. The effect of lactated Ringer's (LR) resuscitation with or without the addition of 2-oxothiazolidine-4-carboxylate (OTC), a cysteine prodrug (enhancing glutathione production) on liver injury, if any, were investigated. Rats in the sham group ( n = 8) and five other groups ( n = 8) underwent femoral artery and vein catheterization and laparotomy. The hemorrhage group was bled 30% of their blood volume and the ischemia group underwent occlusion of the porta hepatis 30 minutes. The hemorrhage-ischemia (HI), LR, and OTC groups underwent both hemorrhage and occlusion. The LR and OTC groups, 30 minutes after hemorrhage, received either LR resuscitation (equivalent to three times the shed blood) or LR resuscitation plus IV OTC (100 mg/kg before clamping and 100 mg/kg after de-clamping). Porta hepatis occlusion in the presence of hypovolemia (HI group) caused an increase in serum ALT, plasma MDA, liver MDA, and base deficit and a decrease in blood pH levels. LR resuscitation lowered only MDA (plasma and liver) and base deficit but did not reduce ALT and increase blood pH. Although liver GSH did not change, OTC kept all parameters at control levels. OTC prevents the deleterious effects of total hepatic inflow occlusion under hypovolemic conditions, but this does not occur through enhancement liver glutathione production. OTC may protect the liver by accelerating hepatic glutathione turnover, but further studies are needed to explain its mechanism of action.
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ABSTRACT: Little is known about the changes in the hepatic microcirculation and the leukocyte-endothelial adhesion processes during the early reperfusion period after resuscitation in hemorrhagic shock. P-selectin and its natural ligand Sialyl Lewis(x) (SLe(x)) are involved in the early stages of reperfusion events leading to neutrophil migration. Therefore, the aim of this study was to investigate the effect of the administration of CY-1503 [corrected], a synthetic SLe(x) analog, in the liver inflammatory response and neutrophil migration after hemorrhagic shock. Rats, each weighing 275 to 300 grams, were subjected to 60 minutes of pressure controlled hemorrhagic shock. After this period, animals were resuscitated according to the following protocol: shed blood was reinfused to equal 50% of the total volume bled, and the other 50% was replaced with 3x volume of Ringer's lactated solution. Animals were divided into sham and two study groups to receive vehicle (controls) and CY-1503 [corrected] (10 mg/kg intravenously) diluted in 1 mL of normal saline 45 minutes after initiating hemorrhagic shock. The following parameters were analyzed: 7-day survival, liver injury tests, liver tissue myeloperoxidase as an index of neutrophil infiltration, and liver histology. Survival was significantly increased from 48% in the controls to 90% in the CY-1503 [corrected] treated group. Animals treated with the SLe(x) analog showed significantly better mean arterial blood pressure after 15 minutes after resuscitation. Also, the treated group showed a marked decrease in liver enzymes levels at 5 minutes and 4 hours after reperfusion. Neutrophil migration was significantly ameliorated as reflected by decreased myeloperoxidase levels in the SLe(x) analog treated group. Furthermore, we observed improved histologic damage scores in the treated group when compared with controls. The SLe(x) analog, CY-1503 [corrected], had a protective effect in ischemic livers by decreasing neutrophil migration after hemorrhagic shock and resuscitation. This protective effect also resulted in improved survival and mean arterial blood pressure after resuscitation.The Journal of trauma 09/1997; 43(2):313-8. · 2.35 Impact Factor
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ABSTRACT: 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. 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. 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). 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.The Journal of trauma 11/2000; 49(5):879-85. · 2.35 Impact Factor
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ABSTRACT: Disturbances of the thiol metabolism of acinar cells may play a role in the pathophysiology of acute pancreatitis. Cerulein-induced pancreatitis causes depletion of glutathione. The entire pancreatic thiol status was assessed in this model. The potential benefit of augmentation of pancreatic glutathione by L-2-oxothiazolidine-4-carboxylate (OTC) for the course of pancreatitis was determined. Mice were treated with cerulein (50 microg/kg) and with or without administration of OTC (6.5 and 20 mmol/kg, respectively). Pancreatic tissue was analyzed for reduced and oxidized glutathione, nonprotein thiol, mixed disulfide, protein thiol, and protein disulfide. Histopathology and serum amylase were also assessed. Levels of all thiol compounds were altered profoundly at a different rate during pancreatitis. OTC caused an increase of 60% in pancreatic glutathione. Its administration at 20 mmol/kg attenuated the decrease of pancreatic glutathione and protein thiol until 8 hours and blunted the cerulein-induced increase in amylase activity and histopathologic damage. At 6.5 mmol/kg, OTC failed to show effects on all parameters. OTC administered in a prophylactic protocol dose-dependently exerted beneficial effects in cerulein-induced pancreatitis in mice despite only transient influence on pancreatic thiol compounds. Thiols (e.g., reduced glutathione) and their corresponding disulfides are critically involved in the pathophysiology of cerulein-induced pancreatitis.Gastroenterology 05/1997; 112(5):1681-91. · 12.82 Impact Factor