Gadolinium chloride inhibits lipopolysaccharide-induced mortality and in vivo prostaglandin E2 release by splenic macrophages

The monocytic phagocytic system, consisting primarily of tissue macrophages of the liver and spleen, produces prostaglandin E₂ (PGE₂), a modulator of the septic response. Macrophages are known to internalize gadolinium chloride (GD), a lanthanide metal, which inhibits phagocytic function. Thus we studied the effect of in vivo GD on lipopolysacchride (LPS)-induced mortality and on LPS-stimuIated PGE₂ release by cultured splenic macrophages. GD (7 mg/kg intravenously) given on the two days prior to LPS challenge (30 mg/kg intravenously) completely prevented the uniform mortality in rats. This protective effect was transient since rechallenge with LPS 10 days later was uniformly lethal. Previous work in this laboratory has established a critical role of arginine concentration on macrophage behavior in vitro. Therefore, to establish culture conditions reflective of the milieu within the portal venous system, alanine and arginine levels were measured in the portal and hepatic veins of normal and endotoxemic (LPS, 10 mg/kg intraperitoneally) rats. In contrast to alanine levels, which were not altered by endotoxemia, there was a reduction of arginine concentrations from a range of 50 to 250 μmol/L in normal rats to a range of 10 to 50 μmol/L after LPS challenge. Consequently subsequent in vitro assays of splenic macrophage secretory behavior were performed in concentrations of 1200 μmol/L arginine (in standard RPMI-1640), as well as in concentrations reflective of physiologic arginine levels (10 and 100 μmol/L in modified RPMI-1640). Rat splenic macrophages harvested after two consecutive days of either in vivo saline or GD injection (7 mg/kg intravenously) were stimulated with LPS (0.025 to 2.5 μg/ml). At 72 hours of culture, the release of PGE₂ by splenic macrophages from GD-treated rats was significantly (P<0.0001) reduced at all LPS concentrations. Increased PGE₂ production was not present when the splenic macrophages were cultured in the supraphysiologic arginine (1200 μmol/L) concentration. The results demonstrate the relevance of physiologic arginine concentrations in cell culture studies and suggest that the protection conferred by GD against septic mortality may be related to downregulation of the release of immunosuppressive PGE₂ by the monocytic phagocytic system. Supported by the following grants: NIH RO1 28480, the Association for Academic Surgery, and the American Liver Foundation. Presented at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20, 1998.     

N-acetylcysteine improves intestinal barrier in partially hepatectomized rats

BACKGROUND: Translocating enteric bacteria play an important role in the development of infections following partial hepatectomy. The intestine itself is the first line of defence against bacterial translocation (BT). We investigated the effect of N-acetylcysteine (NAC) on BT and the intestinal wall. METHODS: We compared four groups of Sprague-Dawley male rats (eight in each group): sham, sham plus preoperative single dose of NAC, partial hepatectomy and partial hepatectomy plus preoperative single dose of NAC. Microorganism count in the tissues and the glutathione and malondialdehyte contents of the intestinal wall were studied at the end of the 24th hour. RESULTS: Bacterial growth was observed in the spleen and mesenteric lymph nodes in the sham group. There was bacterial growth in all the samples of the partial hepatectomy group. Differences were significant except in atrial and portal blood counts. In the partial hepatectomy plus NAC treatment group, counts were significantly low in all, except atrial and portal blood samples. The malondialdehyte level in the intestinal wall was 35.38 +/- 10.27 in the sham group, increasing significantly in the partial hepatectomy group (69.50 +/- 21.48), and decreasing in the partial hepatectomy plus NAC treatment group (35.63 +/- 14.12). Glutathione levels decreased significantly in the partial hepatectomy group and increased with preoperative single-dose NAC. CONCLUSION: Partial hepatectomy resulted in oxidative disturbances in intestinal wall, which in turn gave rise to BT. Parenteral NAC protects the intestinal wall from oxidative injury and attenuates BT.     

Laser enhancement in hepatic regeneration for partially hepatectomized rats

BACKGROUND AND OBJECTIVE: The bio-stimulation effect of laser has been observed in many areas of Medicine. However, there are a few works which investigate its use for liver regeneration. Most of their results were inconclusive due to the use of high power lasers. This work was carried out to investigate the bio-stimulation effect of laser in liver regeneration using low power lasers. STUDY DESIGN/MATERIALS AND METHODS: We used Wistar male rats, which were irradiated with laser light (wavelength 590 nm and intensity of 50 mW/cm(2)) for 5 minutes after 70% hepatectomy. The respiratory mitochondrial activity, the serum level of aminotransferase and the PCNA were measured. RESULTS: Our results show a dramatic increase in the mitochondrial activity for the laser treated group at 24 hours after the hepatectomy. CONCLUSIONS: We conclude that the laser promotes a bio-stimulation effect on the early stages of liver regeneration without any detectable damage of the cells.     

Bile secretion and liver regeneration in partially hepatectomized rats.

OBJECTIVE: The purpose of this research was to study the correlation between bile secretion and the liver regeneration in the partially hepatectomized rat. SUMMARY BACKGROUND DATA: Significant alteration in bile formation and secretion is expected in the liver after hepatectomy. There is scant literature, however, about the effects of liver regeneration in bile secretion. METHODS: The work was done in rats with 50% hepatectomy, 75% hepatectomy, and sham operation as the control. A chronic common bile duct fistula and a duodenal cannula were established for bile collection and the sample analysis on days 1, 3, 5, 7, and 9. RESULTS: With size reduced in the liver after 50% and 75% hepatectomy, the total bile volume decreased 45.9% and 51.5%, bile salt independent flow decreased 59.3% and 64.9%, bile salt secretion rate decreased 36.1% and 43.4%, bile salt basal synthesis rate decreased 52.3% and 56.4%, phospholipid secretion rate decreased 52.6% and 68.0%, and cholesterol secretion rate decreased 54.3% and 72.4% from control on day 1, respectively. All changes returned to the control level in 3 to 9 days with accompanying increasing liver size during regeneration. CONCLUSION: Alterations of total bile flow, bile salt independent flow, bile salt secretion rate, bile salt basal synthesis rate, and biliary lipid secretion after partial hepatectomy correlate with the liver regeneration rate in rats. Partial hepatectomy reduces the bile salt independent fraction calculated as per 100 g body weight rather than the dependent fraction. The study of bile salt and biliary lipid secretion is a useful method for monitoring synthetic function in liver regeneration in vivo.     

Local treatment of generalised peritonitis in rats; effects on bacteria, endotoxin and mortality.

OBJECTIVE: To assess the effect of debridement, intraoperative lavage with saline, and additional instillation of taurolidine or imipenem/cilastatin in rats with faecal peritonitis. DESIGN: Laboratory study. SETTING: University hospital, The Netherlands. MATERIAL: 60 male Wistar rats. INTERVENTIONS: Rats were given an intraperitoneal injection of a faecal suspension containing Escherichia coli and Bacteroides fragilis. Six groups of 10: sham operation, debridement, debridement with saline lavage, debridement with saline lavage with intraperitoneal instillation of saline or taurolidine, or imipenem/cilastatin, were studied. MAIN OUTCOME MEASURES: Bacterial growth and endotoxin concentration in abdominal exudate and plasma, abscess formation, and mortality. RESULTS: Debridement temporarily reduced bacterial growth and the concentration of endotoxin in abdominal exudate, and delayed mortality. Lavage with saline further reduced bacterial growth and the endotoxin concentration. It also reduced the plasma endotoxin concentration, and mortality. Additional instillation of taurolidine did not reduce bacterial growth, but did initially reduce the endotoxin concentration in abdominal exudate and plasma. Instillation of imipenem/cilastatin, after debridement and lavage, significantly reduced all variables measured. CONCLUSION: In rats with faecal peritonitis, debridement, lavage with saline, and additional instillation of imipenem/cilastatin, all have cumulatively reducing effect on bacterial growth, endotoxin concentrations, abscess formation, and mortality. Instillation of taurolidine reduces only the amount of endotoxin.     

Inosine infusion prevents mortality in endotoxic shock

BACKGROUND: Substances that inhibit Na/K ATPase activity appear in plasma during severe septic shock causing Na and fluid to move into cells and K to move out, resulting in cell swelling and an elevation of plasma K. These changes contribute to the morbidity of sepsis. Recently, we reported that inosine and other purine nucleosides stimulate Na/K ATPase activity, prolong survival in hemorrhagic shock, and lower the plasma potassium in that condition. Here, we determine whether inosine prolongs survival in lipopolysaccharide-induced sepsis shock. METHODS: Pentobarbital-anesthetized rats underwent cannulation of a femoral artery and vein, and lipopolysaccharide was injected by intravenous bolus (10 mg/kg). Rats were than resuscitated (5 mL/hr) with inosine (5 mmol/L) in saline, saline alone, inosine with S-4-nitrobenzyl-6-thioinosine (NBTI, 10 micromol/L, an equilibrative nucleoside transporter blocker), NBTI alone, or no resuscitation. RESULTS: Inosine significantly and dramatically prolongs survival of rats in endotoxic shock as compared with saline resuscitation or to no resuscitation. Furthermore, resuscitation with NBTI (10 micromol/L) prevented prolonged survival with inosine. CONCLUSION: Inosine prevents mortality in lipopolysaccharide-induced septic shock in rats. The mechanism of action must be intracellular, as blockers of the equilibrative nucleoside transporter prevented prolonged survival with inosine.     

Spectral response for laser enhancement in hepatic regeneration for hepatectomized rats

BACKGROUND AND OBJECTIVES: The low intensity laser therapy (LILT) has been widely used in all medical fields due to its therapeutic effects in reparative process, pain relief, and biostimulation. Even though there is a therapeutic window of wavelengths for clinical application, little has been done concerning the frequency spectrum response to biological effects. In this work, we investigate the dependence of different wavelengths irradiation in the enhancement of the tissue regeneration after partial hepatectomy in Wistar rats. STUDY DESIGN/MATERIALS AND METHODS: The proliferating cell nuclear antigen (PCNA) labeling index and the respiratory control (oxygen consumption in extracted mitochondria) were the tests used to evaluate the liver regeneration after laser irradiation with different wavelengths. RESULTS AND CONCLUSIONS: The results show a correlated spectral response that can be explained based on the combined effect of light penetration on biological tissues and the biomolecular excitation efficiency for each wavelength used.     

Surgical stress reduces mortality from endotoxin shock

BACKGROUND AND AIM: Surgical stress has been considered a preliminary to multiple organ failure through what has been termed a "two-hit" mechanism. Recent evidence, however, suggests that such stress has a beneficial influence in reducing endotoxin [lipopolysaccharide (LPS)]-mediated lethality. This study has been an effort to clarify whether and how LPS-mediated septic shock is prevented by a previous insult with mild (laparotomy) or severe (hepatectomy) surgical stress. METHODS: LPS was injected intraperitoneally into mice after two-thirds hepatectomy or laparotomy only. Survival rates, and protein and messenger RNA (mRNA) levels for tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured. RESULTS: Most of the unoperated control mice died within 3 days after the LPS challenge. Mortality following LPS injection was reduced after laparotomy only or hepatectomy (P<0.05). A significant reduction in the mortality was observed from 2 days to 7 days after laparotomy only, and from 2 days to 4 weeks after hepatectomy. Correspondingly, the increase in the serum levels of TNF-alpha and IL-6 induced by the LPS injection was partially impaired by either laparotomy only or hepatectomy at an early (2 days) postoperative stage (P<0.05). At a later (7 days) stage, however, the serum level of IL-6 and its mRNA level in the spleen were elevated after the LPS challenge more quickly in the hepatectomy group than in the unoperated control group ( P<0.05). CONCLUSION: Surgical stress reduces LPS-induced lethality through biphasically regulating the levels of TNF-alpha and IL-6 production.     

Experimental study of endotoxemia and reticuloendothelial system in hepatectomized cirrhotic rats

To investigate acute hepatic failure associated with endotoxemia and reticuloendothelial system (RES) in hepatectomized cirrhotic patients, lipopolysaccharide (LPS) at the dose of 0.2 micrograms/100gBW was injected intravenously into the 70% hepatectomized three groups of rats as follows; LC: rats with thioacetamide-induced liver cirrhosis, Control: rats with normal liver, LC + FN: cirrhotic rats with intravenous supplementation of fibronectin. 1) The survival rates at 24 hours after hepatectomy of each group of LC, Control and LC + FN were 0%, 100%, and 80%, respectively. Residual liver of group-LC revealed massive necrosis in histological study. 2) Phagocytic index (K) of injected 3H-labeled LPS were 0.100/min, 0.155/min and 0.146/min, respectively. 3) Uptake of injected 3H-labeled LPS at 15 minutes after injection was remarkably elevated into the liver compared with the lung and spleen in each group. Also uptakes into the liver per gram of tissue were 0.96% ID/g, 3.00% ID/g and 1.46% ID/g, respectively, and those per total organ were 5.95% ID/TO, 8.20% ID/TO and 9.21% ID/TO, respectively. 4) Level of plasma fibronectin decreased and that of serum total bile acid increased remarkably after injection of LPS in group-LC compared with the others. These results suggest the mortality of hepatic necrosis by LPS in group-LC is attributed to markedly reduced RES function especially in the liver, and supplementation of fibronectin decreases the mortality by enhancing RES function.     

The effect of denervation on liver regeneration in partially hepatectomized rats

BACKGROUND/AIM: In a partial liver transplantation, the dissected hepatic nerves are left unrepaired during active liver regeneration. In fact, the pathophysiological influence of such hepatic denervation on liver regeneration has not yet been fully clarified. The aim of the present study is to elucidate the effect of total hepatic denervation on liver regeneration. METHODS: Experiment 1: To confirm the effect of hepatic denervation, the hepatic contents of norepinephrine were measured in both denervated (n = 5) and sham (n = 5) rats. The changes in the hepatic microcirculation were also measured in both denervated (n = 5) and sham (n = 5) rats. Experiment 2: The rats (n = 80) were randomly assigned to two groups: DN group (n = 40); hepatic denervation followed by a partial hepatectomy (PH). Control group (n = 40); sham hepatic denervation followed by PH. In both groups, the animals were killed at 12, 24, 36, 48, 72, 120, and 168 h after PH, respectively. The liver to body weight ratio and the proliferating cell nuclear antigen (PCNA) labeling index were measured at each time point. RESULTS: Experiment 1: Nearly a total depletion of norepinephrine (<99%) was observed in the DN rats. In addition, the hepatic tissue blood flow significantly increased in the DN rats. Experiment 2: The liver to body weight ratio of the DN group was also significantly higher than that of the control group at 168 h (P < 0.05). The PCNA labeling index peaked between 24 and 36 h in the control group, while that in the DN group showed a delayed peak. At 72 and 120 h, the PCNA labeling index was significantly higher in the DN group than in the control group (P < 0.05). CONCLUSION: Total hepatic denervation was thus found to enhance liver regeneration after a partial hepatectomy. This phenomenon is partially triggered by the increased hepatic blood flow to the remnant liver.     

Functional heterogeneity of the kupffer cell population is involved in the mechanism of gadolinium chloride in rats administered endotoxin

BACKGROUND: The purpose of this study was to determine if evidence of functional heterogeneity between subtypes of the Kupffer cell (KC) may be involved in the mechanism of the protective effect of gadolinium chloride (GdCl3) in endotoxemia. METHODS: Rats pretreated with or without GdCl3 were administered lipopolysaccharide (LPS) or vehicle. Serum and liver tissues were collected after LPS administration for cytokine measurements and pathological and immunohistochemical evaluation. RESULTS: After LPS administration, increases in expression of TNF-alpha and IL-6 mRNA in the liver were blunted significantly by GdCl3. In control liver tissue, ED2-positive cells were a predominant fraction, with a few ED1-positive cells, and GdCl3 eliminated only ED2-positive cells. Further, ED2-positive cells were larger in size than ED1-positive ones. Importantly, the number of ED1-positive cells in the liver was increased about threefold in the control group but not in the GdCl3 group after LPS injection. Intermediate or large KCs isolated by counterflow centrifugal elutriation showed greater capacity for phagocytosis and production of superoxide and TNF-alpha than small ones. In contrast, IL-6 production was increased to a greater extent in small than in intermediate or large cells. GdCl3 eliminated the intermediate or large KC subpopulation predominantly. CONCLUSION: Collectively, functional heterogeneity of the KC population was involved in the mechanism of the protective effects of GdCl3 in endotoxemia. TNF-alpha derived from activated intermediate or large KCs may activate small KCs and the latter may be recruited to other organs, such as lungs and kidneys, and produce a large amount of IL-6, leading to multiple organ failure.     

Effects of postoperative adjuvant chemotherapy on liver regeneration in partially hepatectomized rats

Five-fluorouracil (5-FU) was given to rats at various periods following two-thirds hepatectomy and the effects of this drug on the regenerating liver were investigated. In one group of rats, two-thirds hepatectomy was carried out (Group I). In four other groups, 20 mg/kg 5-FU was given intravenously three times: 0, 24, 48 hours (Group II); 12, 36, 60 hours (Group III); 24, 48, 72 hours (Group IV); and 3, 4, 5 days (Group V) after the same operation. The peaks of DNA synthesis and mitoses of liver cells were noted on the first postoperative day in Groups I, IV and V. Persistent suppression and delay of DNA synthesis was induced in Groups II and III, while in Group IV, DNA synthesis and liver cell divisions were suppressed temporarily after the drug administration but recovered thereafter. There was no significant suppression in Group V. The serum albumin levels and survival rates paralleled the DNA synthesis. These results indicate that in case of postoperative adjuvant chemotherapy, great care must be directed to the time when DNA synthesis and mitosis of hepatocytes have not yet reached their peaks, because adjuvant chemotherapy in this period may be life-threatening.     

Enhancement of portal blood flow by ursodesoxycholic acid in partially hepatectomized rats

Portal venous flow (PVF) was examined after portal injection of ursodesoxycholic acid (URSO) in rats that were partially hepatectomized by either 40% or 66%. URSO (10 mg/kg per minute) was injected into the portal vein and was thereafter observed to increase PVF concomitantly with a fall in portal venous pressure (PVP) in control animals. The increase in PVF in response to URSO was dose-dependent. In hepatectomized rats, the PVF response was augmented when the same dose of URSO was portally injected, and the magnitude of response was enhanced in proportion to the volume of liver resected. These results suggest that URSO increases PVF through vasodilation of the portal vessels, and therefore URSO is considered to increase PVF potently in a partially hepatectomized condition.     

Effects of postoperative adjuvant chemotherapy on liver regeneration in partially hepatectomized rats

Five-fluorouracil (5-FU) was given to rats at various periods following two-thirds hepatectomy and the effects of this drug on the regenerating liver were investigated. In one group of rats, two-thirds hepatectomy was carried out (Group I). In four other groups, 20mg/kg 5-FU was given intravenously three times: 0, 24, 48 hours (Group II); 12, 36, 60 hours (Group III); 24, 48, 72 hours (Group IV); and 3, 4, 5 days (Group V) after the same operation. The peaks of DNA synthesis and mitoses of liver cells were noted on the first postoperative day in Groups I, IV and V. Persistent suppression and delay of DNA synthesis was induced in Groups II and III, while in Group IV, DNA synthesis and liver cell divisions were suppressed temporarily after the drug administration but recovered thereafter. There was no significant suppression in Group V. The serum albumin levels and survival rates paralleled the DNA synthesis. These results indicate that in case of postoperative adjuvant chemotherapy, great care must be directed to the time when DNA synthesis and mitosis of hepatocytes have not yet reached their peaks, because adjuvant chemotherapy in this period may be life-threatening.     

Influences of ciclosporin pretherapy on 90% hepatectomized rats.

We studied the effect of ciclosporin (Cs) on rats which underwent a 90% hepatectomy. Rats were divided into two groups: group 1 (without Cs pretreatment) and group 2 (with Cs pretreatment). Animals were given a 4-day treatment of Cs (10 mg/kg/day) prior to hepatectomy. The 1-week survival, serum biochemistry and parameters for hepatocyte proliferation (indices for mitosis and 5-bromo-2-deoxyuridine uptake) were serially investigated. Although Cs pretherapy significantly upregulated liver cell proliferation in group 2, there was no improvement in the survival rate of the immunosuppressed animals (group 2) compared to the controls (group 1). The implications of Cs pretherapy are discussed in the setting of extensive hepatectomy.     

Changes in lysosomal enzyme and fragility of pancreatic acinar cells in hepatectomized rats

To explore the cellular and lysosomal fragility of pancreatic acinar cells in both the early and recovering stages after partial hepatectomy, we evaluated the changes in the pancreatic water content, redistribution of lysosomal enzyme, lysosomal fragility in acinar cells, and lactate dehydrogenese (LDH) discharge from acinar cells 4 days and 8 days after about 70% hepatectomy in rats. In the early stage (4 days) after hepatecotmy, the pancreatic water content was significantly greater than that in sham-operated or normal rats. Both the LDH discharge and lysosomal fragility were also significantly higher than those in the sham-operated and normal rats. Redistribution of lysosomal enzyme was also found in this early stage. In the recovering stage (8 days) after hepatectomy, these parameters tended to return to the preoperative levels (normal rats). These results indicate that the cellular fragility of acinar cells is increased in the early stage after hepatectomy. Lysosomal fragility seems to be related to this cellular fragility of acinar cells in the early stage after hepatectomy.     

Effects of a nucleoside and nucleotide mixture on metabolism in hepatectomized rats

In the present experiment, the effect of a nucleoside-based mixture (OG-VI) on protein synthesis was evaluated. Twenty male Wistar rats weighing about 200g underwent 70% hepatectomy by the Higgins-Anderson's method. All animals were administered standard TPN solution just after operation. The control group received only standard TPN (S-TPN) and the experimental group was given TPN containing 13% v/v of OG-VI (OG-TPN). The rates of whole body protein turnover, synthesis and breakdown measured by the Picou & Taylor-Roberts method with 15N-glycine on the 3rd day after operation. Nitrogen balance on the 1st and 3rd postoperative day and the cumulative nitrogen balance in the OG-TPN group were significantly higher than in controls. Moreover, in the OG-TPN group, protein turnover and protein synthesis were significantly more increased than in the control group. It was thus concluded that the increased protein synthesis, rather than the alteration in protein breakdown, accounted for the good nitrogen balance in the OG-TPN group. The present results strongly suggest that the OG-VI nucleoside and nucleotide mixture improves protein metabolism in hepatectomized rats and helps promoting protein synthesis and turnover after surgical stress.     

Carbon dioxide pneumoperitoneum prevents mortality from sepsis

Background Carbon dioxide (CO₂) pneumoperitoneum has been shown to attenuate the inflammatory response after laparoscopy. This study tested the hypothesis that abdominal insufflation with CO₂ improves survival in an animal model of sepsis and investigated the associated mechanism. Methods The effect of CO₂, helium, and air pneumoperitoneum on mortality was studied by inducing sepsis in 143 rats via intravenous injection of lipopolysaccharide (LPS). To test the protective effect of CO₂ in the setting of a laparotomy, an additional 65 animals were subjected to CO₂ pneumoperitoneum, helium pneumoperitoneum, or the control condition after laparotomy and intraperitoneal LPS injection. The mechanism of CO₂ protection was investigated in another 84 animals. Statistical significance was determined via Kaplan– Meier analysis for survival and analysis of variance (ANOVA) for serum cytokines. Results Among rats with LPS-induced sepsis, CO₂ pneumoperitoneum increased survival to 78%, as compared with using helium pneumoperitoneum (52%; p < 0.05), air pneumoperitoneum (55%; p = 0.09), anesthesia control (50%; p < 0.05), and LPS-only control (42%; p < 0.01). Carbon dioxide insufflation also significantly increased survival over the control condition (85% vs 25%; p < 0.05) among laparotomized septic animals, whereas helium insufflation did not (65% survival). Carbon dioxide insufflation increased plasma interleukin-10 (IL-10) levels by 35% compared with helium pneumoperitoneum (p < 0.05), and by 34% compared with anesthesia control (p < 0.05) 90 min after LPS stimulation. Carbon dioxide pneumoperitoneum resulted in a threefold reduction in tumor necrosis factor-α (TNF-α) compared with helium pneumoperitoneum (p < 0.05), and a sixfold reduction with anesthesia control (p < 0.001). Conclusion Abdominal insufflation with CO₂, but not helium or air, significantly reduces mortality among animals with LPS-induced sepsis. Furthermore, CO₂ pneumoperitoneum rescues animals from abdominal sepsis after a laparotomy. Because IL-10 is known to downregulate TNF-α, the increase in IL-10 and the decrease in TNF-α found among the CO₂-insufflated animals in our study provide evidence for a mechanism whereby CO₂ pneumoperitoneum reduces mortality via IL-10-mediated downregulation of TNF-α. Supported by R01-GM062899-02, National Institutes of Health, Bethesda, MD. Presented at the annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), Ft. Lauderdale, Florida, 13–16 April 2005     

Melatonin prevents acetaminophen-induced nephrotoxicity in rats

Nephrotoxicity is a major complication of acetaminophen (APAP), a widely used analgesic and antipyretic drug, and there is no specific treatment for APAP-induced renal damage. It has been reported that reactive oxygen metabolites or free radicals are important mediators of APAP toxicity. In this study, the protective role of melatonin (MLT) on APAP-induced nephrotoxicity was investigated in rats. For this purpose, nephrotoxicity was induced in male Wistar albino rats by intraperitoneal (i.p.) administration of a single dose of 1,000 mg/kg APAP. Some of these rats also received i.p. melatonin (10 mg/kg) 20 min after administration of APAP. The rats were sacrificed 24 h after administration of APAP. Urea and creatinine levels were measured in the blood, and levels of malondialdehyde (MDA) and glutathione (GSH), and glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activity were determined in renal tissue. Serum urea and creatinine levels increased significantly as a result of APAP nephrotoxicity. A significant increase in MDA and decreases in GSH level and GSH-Px, CAT, and SOD activity indicated that APAP-induced renal damage was mediated through oxidative stress. Significant beneficial changes were noted in serum and tissue oxidative stress indicators in rats treated with MLT. These biochemical observations were supplemented by histopathological examination of kidney sections, which revealed that MLT also reduced the severity of APAP-induced histological alterations in the kidney. These results indicate that administration of APAP causes oxidative stress to renal tissue and that MLT protects against the oxidative damage associated with APAP.