Splenectomy-reduced hepatic injury induced by ischemia/reperfusion in the rat

Abstract: In the present study, we investigated the role of the spleen in experimental hepatic ischemia/reperfusion in the rat. After a 90-min period of ischemia in the left and middle hepatic lobes, the ischemia was released and the liver was reperfused for up to 24 h. Plasma alanine aminotransferase reached a peak 3 h after the onset of reperfusion, and gradually decreased thereafter. A histological examination revealed evidence of hepatocellular necrosis and degeneration, especially 24 h after the onset of reperfusion. In addition, there was a noticeable accumulation of polymorphonuclear cells in the liver following ischemia/reperfusion. A splenectomy performed just prior to ischemia/reperfusion reduced both biochemical and histological hepatocellular injury. The number of polymorphonuclear cells in the liver following ischemia/reperfusion was significantly reduced in rats subjected to splenectomy, suggesting that the increase in polymorphonuclear cells may contribute to liver injury. The number of mononuclear cells also increased in the marginal zones of the spleen following ischemia/reperfusion, and appeared to be derived from the splenic monocyte/macrophage population, based on immunohistochemical studies. The spleen plays an important role in the pathogenesis of hepatic ischemia/reperfusion injury and the splenic monocyte/macrophage population contributes to liver damage.     

Discovery of Novel SPAK Inhibitors That Block WNK Kinase Signaling to Cation Chloride Transporters

Upon activation by with-no-lysine kinases, STE20/SPS1-related proline–alanine-rich protein kinase (SPAK) phosphorylates and activates SLC12A transporters such as the Na⁺-Cl⁻ cotransporter (NCC) and Na⁺-K⁺-2Cl⁻ cotransporter type 1 (NKCC1) and type 2 (NKCC2); these transporters have important roles in regulating BP through NaCl reabsorption and vasoconstriction. SPAK knockout mice are viable and display hypotension with decreased activity (phosphorylation) of NCC and NKCC1 in the kidneys and aorta, respectively. Therefore, agents that inhibit SPAK activity could be a new class of antihypertensive drugs with dual actions (i.e., NaCl diuresis and vasodilation). In this study, we developed a new ELISA-based screening system to find novel SPAK inhibitors and screened >20,000 small-molecule compounds. Furthermore, we used a drug repositioning strategy to identify existing drugs that inhibit SPAK activity. As a result, we discovered one small-molecule compound (Stock 1S-14279) and an antiparasitic agent (Closantel) that inhibited SPAK-regulated phosphorylation and activation of NCC and NKCC1 in vitro and in mice. Notably, these compounds had structural similarity and inhibited SPAK in an ATP-insensitive manner. We propose that the two compounds found in this study may have great potential as novel antihypertensive drugs.     

The effect of bilirubin on biliary lipid secretion: Analysis by horseradish peroxidase associated intrahepatic vesicular transport system

The mechanism of biliary lipid secretion is still controverial and there is no definite information regarding how bilirubin inhibits biliary phospholipid and cholesterol secretions without affecting bile salt secretion. In this study, the effects of biliribin on intrahepatic vesicular transport and biliary lipid secretion were examined using bile-fistula rats. Horseradish peroxidase (HRP) was used as a tracer of intrahepatic vesicular transport. Bilirubin (5mg/100g BW) and/or HRP (5mg/100gBW) were injected through the mesenteric vein. Bile flow, biliary bile acid, biliary phospholipid and cholesterol outputs were examined in saline, HRP and HRP+bilirubin groups, respectively. Bile flow and biliary bile acid output were not affected by bilirubin administration. Biliary phospholipid and cholesterol as well as biliary HRP outputs were inhibited just after bilirubin administration, 42.8±6.1 SD% 47.7±5.1 SD%, and 33.4±3.8 SD%, respectively. These results suggested the participation of intrahepatic vesicular transport system in the inhibition of biliary lipid secretion by bilirubin and in its secretory mechanism. This study was partially funded by Uehara Life Science Foundation.     

Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C. A long term follow-up study after histologic diagnosis

BACKGROUND: Hepatocellular carcinoma (HCC) occurs more frequently in patients with hepatitis C virus (HCV)-related chronic liver disease than those with hepatitis B virus-related disease. It is important to assess the factors affecting the development of HCC. METHODS: A long term follow-up study involving patients with chronic HCV was performed retrospectively. A total of 153 patients diagnosed between June 1981 and November 1990 with chronic HCV with or without cirrhosis by liver biopsy were enrolled in a long term follow-up study (average, 99.4 months) and the cumulative incidence rate of HCC and factors affecting the appearance of HCC were examined. RESULTS: The 5-year cumulative incidence rate was 9%, the 10-year cumulative incidence rate was 23%, and the 15-year cumulative incidence rate was 42%. The annual rate of incidence increased as the follow-up period progressed. The authors selected ten variables and investigated their effect on the incidence rate of HCC, including age, gender, habitual heavy drinking, positivity of antibody against hepatitis B virus surface antigen, treatment with interferon (IFN) during the follow-up period, maximum and minimum serum alanine aminotransferase levels during the follow-up period, histologic staging, grading, and irregular regeneration of hepatocytes. Of the 10 variables, age (> 50 years), habitual heavy drinking, and histologic staging were determined to be independent risk factors according to multivariate Cox proportional hazards regression analysis. IFN therapy by itself was not found to be an independent factor affecting the appearance of HCC. CONCLUSIONS: In patients with chronic HCV, the annual incidence rate of HCC appeared to increase as the follow-up period progressed. According to the results of the current study, the factors that independently affected the development of HCC were age, habitual heavy drinking, and histologic staging.     

Portal vein aneurysm: report of six cases and review of the literature

Portal vein aneurysm is very rare, and its relation to portal hypertension has been emphasized. We report six cases of portal vein aneurysm (five extrahepatic and one intrahepatic). All patients were asymptomatic and had no signs suggestive of portal hypertension; the lesion was incidentally detected by ultrasound. Color Doppler sonography showed a constant hepatopetal flow along the aneurysmal wall, which immediately led to the diagnosis. We stress the usefulness of color Doppler sonography for studying the hemodynamics of this vascular anomaly and briefly review the literature. Received: 29 December 1995/Accepted: 14 February 1996