Shinwa Yamada

Provocation of massive hepatic necrosis by endotoxin after partial hepatectomy in rats

When rats received endotoxin 48 hours after two-thirds liver resection, 50% of them died within 12 hours with massive hepatic necrosis at a dose that did not affect sham-operated rats. In the hepatic sinusoids, fibrin deposition and endothelial cell destruction occurred 5 hours after endotoxin administration. When antithrombin III concentrate was infused concomitantly with endotoxin administration, all rats survived 12 hours, and the extent of hepatic necrosis and the deranged serum glutamic pyruvic transaminase values were significantly attenuated at 5 hours compared with those in the control rats. Similar improvements in the incidence of mortality and liver injury were observed after treatment with gum arabic before hepatectomy. The stimulatory state of Kupffer cells based on the ability to produce superoxide anions estimated by formazan deposition after liver perfusion with nitro blue tetrazolium and phorbol myristate acetate was increased between 24 and 72 hours after operation. This increase disappeared after gum arabic treatment. It is concluded that massive hepatic necrosis can occur as a result of sinusoidal fibrin deposition provoked by endotoxin in partially hepatectomized rats. Activated Kupffer cells may contribute to this provocation.

Serum hepatocyte growth factor levels in hepatectomized and nonhepatectomized surgical patients

Serum hepatocyte growth factor levels were measured in hepatectomized and nonhepatectomized surgical patients. The levels were significantly increased and reached a maximum within 7 days after surgery in both groups, returning to preoperative levels 28 days after partial hepatectomy and 7 days after other operations. Multiple regression analysis showed that such maximal hepatocyte growth factor levels were significantly related to having liver cirrhosis and postoperative maximal serum total bilirubin and alanine aminotransferase levels and peripheral white blood cell counts in the hepatectomized group and to postoperative maximal peripheral white blood cell counts and serum C-reactive protein levels in the nonhepatectomized group. However, the levels showed no relation to the resected liver volume and increment of the remaining liver volume 28 days after partial hepatectomy. It is concluded that serum hepatocyte growth factor levels were increased after partial hepatectomy in association with hepatocellular dysfunction and necrosis and systemic inflammation. It is unlikely that the increase was related to liver regeneration.

Intravascular coagulation in the development of massive hepatic necrosis induced by Corynebacterium parvum and endotoxin in rats

When Escherichia coli endotoxin was intravenously injected into rats given killed Corynebacterium parvum 6 days previously, fibrin deposition and endothelial cell injury occurred in hepatic sinusoids at 1.5 h and were intensified thereafter. Serum alanine aminotransferase values were increased along with prothrombin time and decreased plasma levels of antithrombin III and coagulation factor VIII:C at 5 h. Antithrombin III concentrate (plus heparin) or superoxide dismutase infused concurrently with injection of endotoxin significantly attenuated the derangements of these variables and the histologic extent of liver injury at 5 h. Intravascular coagulation, probably developing through the action of superoxide anion, may contribute to the development of massive hepatic necrosis induced by C. parvum and endotoxin in rats.

Glucagon and insulin for the treatment of hepatic failure in dimethylnitrosamine-intoxicated rats

When rats received dimethylnitrosamine every 24 h until death, plus hormone treatment after the first 24 h, the survival was enhanced between 100 and 140 h compared with the control rats, with attenuated derangements of prothrombin time and serum albumin levels at 120 h. In rats given a single dose of dimethylnitrosamine, hepatic DNA synthesis peaked at 48 h. The synthesis was increased after hormone treatment when started immediately, but not when delayed for 24 h. Hormone treatment for 3 days starting 24 h after a single dose of dimethylnitrosamine produced a rapid normalization of decreased hepatic protein content on day 9, although hepatic DNA content was not affected. These results suggest that this treatment is effective for hepatic failure, and the promotion of restoration of liver function is a contributing factor to its effect, in addition to the stimulation of hepatocyte proliferation.

Evidence for potentiation of lipid peroxidation in the rat liver after chronic ethanol feeding

Hepatic steatosis was induced in rats by feeding nutritionally adequate liquid diet containing ethanol as 36% of energy for 4-5 weeks. After 24 h fasting and withdrawal from ethanol, liver ischaemia for 30 min followed by 2 h reperfusion resulted in a significant increase in microsomal lipid peroxide content and a decrease in reduced glutathione content as well as in protein synthesis with a rapid accumulation of triglyceride in the liver. In rats fed a non-ethanol diet or those fed a high-cholesterol diet with hepatic steatosis, however, similar phenomena were not found. These findings suggest that chronic ethanol feeding potentiates hepatic lipid peroxidation.

Enhancement of carbon tetrachloride-induced liver injury by glucagon and insulin treatment

SummaryRats given a dose of carbon tetrachloride (CCl4) immediately received injections of glucagon and insulin every 4h. They frequently died after 4h and showed a significantly higher mortality between 8h and 28h as compared to the control rats where such deaths occurred 16h later. At 8h, the derangements of SGPT values and prothrombin time were significantly greater in the hormone-treated rats than in the control rats. In these CCl4-intoxicated rats, hepatic reduced glutathione content at 4h was significantly reduced after hormone treatment. The treatment significantly enhanced CCl4 metabolism, conversion of14CCl4 into14CO2 in vitro, by microsomes isolated from the liver, whereas it did not affect the microsomal cytochrome P450 content. These results suggest that glucagon and insulin treatment increased CCl4 hepatotoxicity in rats through activating the cytochrome P450-dependent mono-oxygenase system. This would merit consideration for the clinical application of this treatment.

Insulin and glucagon therapy of acute hepatic failure

When insulin and glucagon are administered to rats with severe liver injury, survival is enhanced with an attenuation of the liver injury compared to that of untreated controls. In rats with acute liver injury both hormones produce a rapid normalization of hepatic protein content following initiation of DNA synthesis. When rats receive both hormones after partial hepatectomy, the first burst of DNA synthesis reaches a maximum earlier than that seen in controls. Both hormones enhance the increment of hepatic putrescine essential for DNA synthesis through activation of ornithine decaroxylase and/or spermidine-N1-acetyltransferase. The enhancement of putrescine content by each hormone is additive. Putrescine supplementation promotes hepatic DNA synthesis after hepatectomy. Based on these data, we conclude that a combination of insulin, and glucagon is effective in the therapy of acute hepatic failure in rats. The restoration of liver function as well as the stimulation of liver cell proliferation via putrescine production may contribute to this effect.