Yoshihiro Nakatani

Endothelin-1 plays a major role in portal hypertension of biliary cirrhotic rats through endothelin receptor subtype B together with subtype A in vivo

BACKGROUND/AIMSnEndothelin-1 has been suggested to play a key role in cirrhotic portal hypertension, but a role of its receptors in vivo is not fully elucidated.nnnMETHODSnBiliary cirrhosis was induced by bile duct ligation. Expressions of endothelin-1 and its receptors were evaluated by radioimmunoassay and/or reverse-transcription polymerase chain reaction. Hemodynamics were studied using endothelin receptor agonist or antagonist.nnnRESULTSnPortal pressure and hepatic endothelin-1 concentrations progressively increased in parallel after bile duct ligation. Gene expression of hepatic prepro-endothelin-1 and endothelin B receptor enhanced after bile duct ligation, while that of endothelin A receptor was unchanged. Intraportal administration of endothelin-1 or endothelin B receptor agonist sarafotoxin 6c (0.5 nmol/kg, respectively) progressively raised portal pressure in both sham and cirrhotic rats. Portal hypertensive effect of sarafotoxin 6c was more intense in cirrhotic rats than sham animals. Neither endothelin A receptor antagonist FR139317 (1 mg/kg) nor endothelin B receptor antagonist BQ788 (1 mg/kg) alone ameliorated cirrhotic portal hypertension. Only the combined endothelin A and B blockade was associated with a decrease in portal pressure in cirrhotic rats.nnnCONCLUSIONSnThese results indicate that endothelin-1 plays a major role in cirrhotic portal hypertension through endothelin receptor subtype B together with subtype A in vivo.

The production of tumor necrosis factor-α by macrophages in rats with acute alcohol loading

Background: It is suggested that endotoxin, proinflammatory cytokines, and lipopolysaccharide-binding protein (LBP) play an important role in the development of alcoholic liver disease. Our previous study showed that splenic macrophages were important for endotoxin uptake and excessive production of tumor necrosis factor (TNF) in rats given large amounts of alcohol. To study the pathophysiological roles of macrophages in alcoholic liver diseases, we examined the production of TNF-a by rat Kupffer cells, splenic macrophages, and alveolar macrophages with acute alcohol loading in the presence or absence of LBP. Methods: Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from male Wistar rats given 5 mg/g body weight of ethanol intraperitoneally after an hour. The production of TNF-a by these cells incubated with endotoxin 100 ng/ml in the presence or absence of LBP (1% rat serum) was determined. Results: Acute alcohol loading did not affect the production of TNF-a by Kupffer cells. With acute alcohol loading, splenic macrophages tended to produce more TNF-a. Alveolar macrophages produced more TNF-a than Kupffer cells, and although the production of TNF-a by alveolar macrophages tended to be suppressed by acute alcohol loading, the production of TNF-a by alveolar macrophages still remained high in the presence of rat serum. Conclusions: Splenic macrophages and alveolar macrophages may be related to excessive production of TNF-α in acute alcoholics with endotoxemia.

Hepatic adenomas treated with percutaneous ethanol injection in a patient with glycogen storage disease type Ia

Abstract: We report a 20-year-old man with glycogen storage disease type Ia (GSD Ia) who presented multiple hepatocellular adenomas (HCAs) in 1993 and in whom percutaneous ethanol injection (PEI) was conducted as treatment for some enlarging tumors beneath the liver surface. In a 6-year follow-up period, we observed gradual enlargement of some of the HCAs, and the rapid growth of a newly developed tumor. In August 1996, one slow-growth HCA was 52 mm in diameter and was located beneath the surface of the liver. We conducted PEI therapy to prevent its spontaneous rupture. During the following year, another tumor developed beneath the liver surface, but showed extremely rapid growth, reaching 51 mm in diameter, from being undetectable, within 12 months. PEI therapy was again conducted for this newly developed tumor. Although additional PEI therapy was required for each tumor, because of suspected recurrence, no findings of discrete recurrence have been detected by computed tomography and magnetic resonance imaging for more than 2 years, up to the time of this study. We consider PEI to be a useful and effective therapeutic modality for individual HCAs in patients with GSD Ia.

Effect of prostaglandin e receptor subtype EP4 selective agonist on the secretion of tumor necrosis factor-α by macrophages in acute ethanol-loaded rats

BACKGROUNDnIt is suggested that endotoxin and proinflammatory cytokines play an important role in the development and progression of alcoholic liver disease. Recently, a prostaglandin receptor subtype EP4 agonist with cytoprotective effect has been developed. We examined the efficacy of an EP4 agonist ONO-AE1-437 on tumor necrosis factor-alpha (TNF-alpha) secretion of Kupffer cells, splenic macrophages, and alveolar macrophages in acute ethanol-loaded rats.nnnMETHODSnKupffer cells, splenic macrophages, and alveolar macrophages were isolated from control and acute ethanol-loaded rats (5 mg/g body weight of ethanol, intraperitoneally). After the preculture in the medium that containing 0, 0.1, 1, 10, or 100 nmol/liter of ONO-AE1-437, TNF-alpha secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr.nnnRESULTSnThe amount of TNF-alpha secreted from alveolar macrophages was largest in both the control and the acute ethanol-loaded rats. Acute ethanol load enhances TNF-alpha secretion of splenic macrophages. The addition of ONO-AE1-437 significantly inhibited TNF-alpha secretion of Kupffer cells and splenic macrophages in both the control and the acute ethanol-loaded rats. Alveolar macrophages were less affected.nnnCONCLUSIONSnAn EP4 agonist ONO-AE1-437 suppresses excess TNF-alpha secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.