Hirosumi Oide

Role of Kupffer cells and gut-derived endotoxins in alcoholic liver injury1

The hepatotoxic effects of alcohol have been described in detail, but factors responsible for its hepatotoxicity have only partially been characterized. For example, it is known that chronic ethanol ingestion increases hepatotoxicity and produces fatty liver, hepatitis and cirrhosis. However, acute ethanol consumption reduces endotoxin hepatotoxicity. It now appears that Kupffer cells participate in several aspects of these phenomena. Previously, most studies on the effects of alcohol on liver function have focused chiefly on the hepatocyte. Recently, attention has been directed towards the effect of ethanol ingestion on Kupffer cell function, which is stimulated by gut‐derived endotoxins (lipopolysaccharides) via mechanisms dependent on increased gut permeability and the possible relationship between Kupffer cells and alcohol‐induced liver injury. Here we will review new evidence for the proposal that Kupffer cells and endotoxins play a pivotal role in hepatotoxicity following alcohol exposure, based on studies using the continuous intragastric enteral feeding model developed by Tsukamoto and French and an acute model developed by us.

Basic fibroblast growth factor accelerates gastric mucosal restoration in vitro by promoting mesenchymal cell migration and proliferation.

It has been generally accepted that basic fibroblast growth factor is a potent stimulator of duodenal ulcer healing. However, the detailed mechanism and mode of action of growth factor on gastric ulcer healing is still controversial. Therefore, in the present study, the effects of basic fibroblast growth factor on gastric mucosal repair were studied using an in vitro cultured cell system. Artificial wounds were made in confluent monolayer rabbit gastric fibroblast and epithelial cell sheets by mechanical denudation. Changes in the size of the cell‐free area were analysed quantitatively. Cell proliferation was assessed by BrdU staining. For both cell types, mucosal restoration involved cell migration and proliferation. Although the speed of restoration of epithelial cells was not affected by the addition of basic fibroblast growth factor, it was much faster for epithelial cells than for fibroblasts. Basic fibroblast growth factor accelerated wound repair of fibroblasts but not epithelial cells. Basic fibroblast growth factor accelerated wound repair by stimulating both cell migration and proliferation. Therefore, the effects of basic fibroblast growth factor in peptic ulcer diseases may be mainly due to the stimulation of mesenchymal cells.

Effects of rebamipide on bile acid-induced inhibition of gastric epithelial repair in a rabbit cell culture model

Background: Anti‐ulcer agents exert various functional effects on gastric epithelial cells.

ACTIVATED STELLATE (ITO) CELLS POSSESS VOLTAGE-ACTIVATED CALCIUM CURRENT

We previously reported stellate (Ito) cells possess voltage-activated Ca2+ current. The activation of stellate cells has been indicated to contribute to liver fibrosis and the regulation of hepatic hemodynamics. The aim of this study was to investigate the relationship between voltage-activated Ca2+ current and activation of stellate cells. Voltage-activated Ca2+ current in stellate cells isolated from rats were studied using whole-cell patch clamp technique. L-type voltage-activated Ca2+ current was hardly detected in stellate cells cultured for less than 9 days. Ca2+ current was detected 12.5 and 69% of cells at the 10th and 14th day of culture, respectively. BrdU incorporation indicated cell proliferation was recognized over 50% of cells at the 3rd and 5th day of culture, respectively, then decreased significantly in a time-dependent manner. On the other hand, the expression of alpha-smooth muscle actin indicated cell activation increased from 7th day of culture and collagen type I mRNA appeared remarkably in cells cultured for more than 10 days. In this study, we concluded L-type voltage-activated Ca2+ current was recognized in activated stellate (myofibroblast-like) cells.

Effects of growth factors on aspirin-induced inhibition of wound repair in a rabbit gastric epithelial cell model.

Background: Aspirin is known to cause adverse effects, including gastric mucosal injury, and to retard gastric wound healing. Growth factors including hepatocyte growth factor (HGF), epidermal growth factor (EGF) and insulin‐like growth factor‐I (IGF‐I) have been shown to play an important role in the repair of gastric mucosal injury.

Hepatic stellate cell contraction is inhibited by lipo-prostaglandin E1 in vitro

Prostaglandin E1 (PGE1) has been reported to have, experimentally and clinically, a protective effect against liver damage. This effect may result from the relaxation of hepatic stellate cells, whose contraction induces vasoconstriction of hepatic sinusoids. However, prostaglandins are unstable and a new drug delivery system is necessary to administer a sufficient amount of prostaglandin to achieve a protective effect in the liver. The aim of the study is to investigate the effects of lipo‐prostaglandin E1 (lipo‐PGE1) which has a novel drug delivery system on the stellate cell contraction induced by endothelin‐1 in vitro. Lipo‐PGE1 inhibited endothelin‐1‐induced stellate cell contraction in concentrations of 10, 30 and 50 ng/mL. Therefore, lipo‐PGE1 may show a cytoprotective effect in the liver through the relaxation of stellate cells and an increase in the hepatic sinusoidal blood flow.

Effects of Wortmannin, a Novel Myosin Light-Chain Kinase Inhibitor, on Bile Canalicular Contraction in Vitro and in Vivo

BACKGROUND The cytoskeletal system is believed to play an important role in normal bile formation. The effects of wortmannin, a new myosin light-chain kinase inhibitor, on bile canalicular contraction and bile flow have been observed. METHODS The bile canalicular contraction of cultured hepatocyte doublets was investigated, using an image analyzer with a phase contrast microscope, and the intracellular Ca2+ concentration was measured, using microscopic fluorometry. We also investigated bile flow by in vivo intraportal infusion of the drug in rats. RESULTS Treatment with wortmannin inhibited norepinephrine-induced canalicular contraction and caused a decrease in bile flow without changing systematic and portal blood pressure. Morphologic examination of the electron microscopic study showed that most bile canaliculi were dilated, with loss of microvilli, but no other apparent damage was seen in parenchymal hepatocytes. CONCLUSIONS These data suggest that the integrity of the phosphorylation system of myosin is essential for normal bile flow.

Integrity of myosin light chain kinase is essential for Ito cell contraction

Hepatic sinusoidal Ito cells (fat storing cells) are believed to play a regulatory role on hepatic sinusoidal blood flow through their contraction. The detailed mechanism of contraction of Ito cells, however, is still unknown. The present study was undertaken to clarify the effect of new myosin light chain kinase inhibitor, wortmannin, on Ito cell contraction. Ito cells prepared from rat liver were cultured for 4 days before the study. The contraction of Ito cells, which was monitored and analysed by time‐lapse video tape recording, was triggered by addition of endothelin‐1. Wortmannin pretreatment for 1 h inhibited endothelin‐induced Ito cell contraction dose‐dependently. Therefore, the integrity of the actomyosin system is essential for Ito cell contraction and normal sinusoidal blood flow.

Case Report: Primary Gastric T-cell Lymphoma Accompanied by HTLV-I, HBV and H. pylori Infection

Primary gastrointe stinal lymphomas are the most common forms of extranodal non-Hodgkin’ s lymphoma (NHL), of which almost half are of the gastrointe stinal tract (1, 2). Most primary gastrointe stinal lymphomas are conside red to be of B-cell origin; those of T-cell origin are very rare (3± 8). Only 38 cases of primary gastric T-cell lymphoma have been reported in the lite rature . Recently, T-cell leukemia virus type I (HTLV-I) has received attention as an etiological factor, as approximate ly half of the reported cases are positive for HTLV-1 antibody. Furthermore , the close association of Helicobacter pylori infection with malignant lymphoma also has been recognized. Here we present a case of primary gastric T-cell lymphoma that was positive not only for HTLV-1 antibody but also HBV and H. pylori infection.

Effects of teprenone on gastric epithelial restoration in a rabbit cultured cell model

Abstract: The mechanism of action of gastrocytoprotective agents is not fully understood. We assessed the effects of an anti-ulcer agent, teprenone, and bile acid on epithelial restoration. Teprenone with or without deoxycholic acid was added to a complete confluent cultured gastric epithelial cell sheet after wounding. Restoration was monitored for 48 h, and the wound size was assessed. Migration velocity was measured, and proliferation was detected by sequential staining with bromodeoxyuridine. The labeling index was calculated. Restoration was completed within 48 h in controls, whereas deoxycholic acid retarded repair. The migration velocity was suppressed by deoxycholic acid treatment. The number of proliferative cells peaked at 36 h (labeling index, 1.7%) in controls. In the deoxycholic acid group, the maximal labeling index was 0.5% at 48 h. Teprenone abolished the bile acid-induced retardation. Teprenone showed cytoprotective effects against deoxycholic acid-induced inhibition of epithelial cell migration and proliferation.