Keiichi Hirata

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.

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.

Fat-storing cell abnormalities associated with endothelial cell damage after cold ischemic storage of rat liver in UW solution

Rat liver was stored at 1° C in University of Wisconsin solution, and morphological changes were observed after 12, 18, 24, and 36 hr by transmission electron microscopy. There were two types of endothelial cell damage in the hepatic sinusoids. One was disruption of the endothelial linings, and the other detachment of endothelial cells into the sinusoidal space accompanied by fat-storing cell abnormalities. The former damage was seen after storage longer than 12 hr, while the latter developed after 18 hr even in the hepatic sinusoids with no disruption of the linings. Considering that fat-storing cell damage can produce endothelial cell destruction, this damage should be given attention as one of factors of endothelial cell destruction in the hepatic sinusoids after cold storage of the liver.

Possible contribution of protein kinase C activation to priming for DNA synthesis induced by epidermal growth factor with insulin and its inhibition by plasma membrane in primary cultured rat hepatocytes

In primary cultured rat hepatocytes, DNA synthesis was markedly induced 48 h after plating by epidermal growth factor (EGF) and insulin added at 24 h, but not by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). When EGF and insulin were added at 6 h, DNA synthesis at 30 h was 7% of DNA synthesis seen at 48 h, but became 27% by pretreatment with TPA. The similar pretreatment effect was also seen with vasopressin. Such induction at 30 h was inhibited by rat liver plasma membrane added at 2 h even in the presence of TPA or vasopressin, and also by 1-(5-isoquinolinyl-sulfonyl)-2-methylpiperazine more extensively than N-(2-guanidinoethyl)-5-isoquinolinesulfonamide. These results suggest that DNA synthesis induction by EGF and insulin may require a priming period related to protein kinase C activation in primary cultured rat hepatocytes, which is inhibited by plasma membrane.

Reductions of PDGF and TIMP-1 concentrations in serum contribute to resolutions of fibrosis in chronic hepatitis C patients with sustained response to interferon (IFN) therapy

were found to have advanced liver disease based upon their liver disease evaluation that included a liver biopsy. 3/8 were HCV-AB positive by RIBA technique. 2 had severe portal and peri-portal inflammation with necrosis, while the remaining 6 had cirrhosis. All the liver biopsies had features suggestive of hepatitis C infection. None of the patients had HCV-RNA present in the liver. One patient was found to have a 5cm hepatocellular carcinoma. Six of these 8 patients were found to have an identifiable risk factor for HCV infection. 3 patients had abused alcohol up to 2-3 years before being evaluated. Three patients had an elevated ANA titer of 1:160. The remaining 16/24 (66.7%) patients had mild liver disease based upon their laboratory and pathological evaluations. 7/16 patients were also positive for HCV-AB by RIBA technique. 12 underwent liver biopsies showing only minimal to mild liver disease. Conclusion This experience corroborates the reports in literature that spontaneous HCV-RNA negativity can occur in a few patients exposed to hepatitis C infection during the earlier phase of this infection as a consequence of an effective immune reponse without causing much liver pathology. However, this experience expand prior data by documenting that a few such patients (1.5% overall but 33% of these with resolved infections) have significant liver disease including cirrhosis.

Abstracts of selected papers presented at the 77th General Meeting of the Japanese Society of Gastroenterology

M E E T I N G OF T H E J A P A N E S E S O C I E T Y OF G A S T R O E N T E R O L O G Y March 28-30, 1991-Tokyo, Japan Chairman: Yutaka MATSUO, M.D.