Kimihide Nakamura

Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis

The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF‐β1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH. (HEPATOLOGY 2004.)

Plasma transforming growth factor‐β1 level and efficacy of α‐tocopherol in patients with non‐alcoholic steatohepatitis: a pilot study

Non‐alcoholic steatohepatitis is a distinct entity, characterized by fatty change, lobular inflammation and fibrosis of the liver. Some cases of non‐alcoholic steatohepatitis progress to cirrhosis, but it is not easy to distinguish this disease from non‐alcoholic fatty liver by non‐invasive examinations. No proven therapy for non‐alcoholic steatohepatitis exists. Transforming growth factor‐β1 is implicated in the development of liver fibrosis, and is inhibited by α‐tocopherol (vitamin E) in the liver. Therefore, in this study, the significance of the measurement of the level of plasma transforming growth factor‐β1 and the effect of α‐tocopherol on the clinical course of non‐alcoholic steatohepatitis were investigated.

Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis

Ursodeoxycholic acid (UDCA) has been shown to have beneficial effects on patients with primary biliary cirrhosis, suggesting that UDCA has immunomodulating effects. We investigated the effect of UDCA in patients with autoimmune hepatitis (AIH) which is characterized by immunological abnormalities. Eight patients with type 1 AIH were treated with 600 mg of UDCA per day for 2 years. Based on the criteria of the International Autoimmune Hepatitis Group, five patients were diagnosed as definite and three as probable type 1 AIH. Liver function tests were performed every 4 weeks, before and during UDCA therapy and the serum levels of anti‐nuclear antibodies (ANA), smooth muscle antibodies (SMA), immunoglobulin G and gamma globulin were determined every 3 months. The levels of serum aspartate aminotransferase and alanine aminotransferase significantly decreased from 154 ± 24 IU/L and 170 ± 17 IU/L before UDCA therapy to 31 ± 3 IU/L and 25 ± 5 IU/L (P < 0.001) after 1 year of treatment and 28 ± 2 IU/L and 23 ± 4 IU/L (P < 0.001) after 2 years of treatment. After 2 years of treatment, the levels of serum immunoglobulin G and gamma globulin significantly decreased (P < 0.05) and ANA titres (5/8 patients) were reduced and SMA (3/5. patients) became negative. Furthermore, hepatic histopathological changes of four patients were assessed after 1 year of treatment, and an improvement of intrahepatic inflammation, but not fibrosis, was observed. In conclusion, these results suggest that UDCA has a beneficial therapeutic effect in patients with type 1 autoimmune hepatitis.

High, but not low, molecular weight hyaluronan prevents T-cell-mediated liver injury by reducing proinflammatory cytokines in mice

BackgroundThe extracellular matrix component hyaluronan (HA) modulates the production of various cytokines and chemokines by activated inflammatory cells. In this study, we investigated whether exogenous administration of HA influences T-cell-mediated liver injury and cytokine production.MethodsLiver injury was induced by administration of concanavalin A (Con A) or D-galactosamine/lipopolysaccharide (GalN/LPS), and 0.05%–0.35% (v/v) HA (MW 250, 470, 780, 900, and 1200 kDa) was administered intravenously 18 h before Con A or GalN/LPS injection. Plasma ALT level was determined enzymatically and plasma cytokine levels were determined by ELISA.ResultsThe elevated plasma levels of ALT at 8 h after Con A and at 7 h after GalN/LPS injection were significantly decreased by pretreatment with high molecular weight HAs (780, 900, and 1200 kDa) but not low molecular weight HAs (250 and 470 kDa). High molecular weight HA (900 kDa) significantly reduced plasma tumor necrosis factor-alpha, interferon gamma, macrophage inflammatory protein 2, and interleukin 4 levels after Con A injection. However, this inhibitory effect on plasma cytokines was not observed with low molecular weight HA (250 kDa) pretreatment.ConclusionsThe present results suggest that high molecular weight but not low molecular weight HA prevents liver injury by reducing proinflammatory cytokines in a T-cell-mediated liver injury model.

Macrophage inflammatory protein-2 induced by TNF-α plays a pivotal role in concanavalin A-induced liver injury in mice

Abstract Background/Aims : Macrophage inflammatory protein-2 (MIP-2), one of the CXC chemokines, is involved in the recruitment of neutrophils in several tissue injuries. In this study, we investigated the role of MIP-2 in concanavalin A (Con A)-induced liver injury in mice. Methods : Liver injury was induced by intravenous injection of Con A (15 mg/kg) and plasma alanine aminotransferase (ALT), MIP-2 levels were determined and histological assessment of the liver was performed. Anti-mouse MIP-2 antibody was intravenously administered 30 min before Con A injection. Results : The plasma ALT level significantly elevated and reached a maximum at 8 h after Con A injection. The plasma MIP-2 level was also elevated and reached a peak value at 2 h after Con A injection. The elevated ALT level by Con A injection was significantly inhibited by the MIP-2 antibody. The elevated plasma MIP-2 level after Con A injection was significantly reduced by the tumor necrosis factor alpha (TNF- α ) antibody, and MIP-2 was induced in plasma after recombinant TNF- α injection. Hepatic necrosis and infiltration of neutrophils were observed after Con A injection, and these histological changes were attenuated by the MIP-2 antibody. Conclusions : These findings suggest that Con A induces TNF- α release, and this TNF- α stimulates MIP-2 induction, at least partially contributing to the liver injury mediated through the recruitment of neutrophils.

Effect of central corticotropin-releasing factor on carbon tetrachloride-induced acute liver injury in rats

Central neuropeptides play important roles in many instances of physiological and pathophysiological regulation mediated through the autonomic nervous system. In regard to the hepatobiliary system, several neuropeptides act in the brain to regulate bile secretion, hepatic blood flow, and hepatic proliferation. Stressors and sympathetic nerve activation are reported to exacerbate experimental liver injury. Some stressors are known to stimulate corticotropin-releasing factor (CRF) synthesis in the central nervous system and induce activation of sympathetic nerves in animal models. The effect of intracisternal CRF on carbon tetrachloride (CCl4)-induced acute liver injury was examined in rats. Intracisternal injection of CRF dose dependently enhanced elevation of the serum alanine aminotransferase (ALT) level induced by CCl4. Elevations of serum aspartate aminotransferase, alkaline phosphatase, and total bilirubin levels by CCl4 were also enhanced by intracisternal CRF injection. Intracisternal injection of CRF also aggravated CCl4-induced hepatic histological changes. Intracisternal CRF injection alone did not modify the serum ALT level. Intravenous administration of CRF did not influence CCl4-induced acute liver injury. The aggravating effect of central CRF on CCl4-induced acute liver injury was abolished by denervation of hepatic plexus with phenol and by denervation of noradrenergic fibers with 6-hydroxydopamine treatment but not by hepatic branch vagotomy or atropine treatment. These results suggest that CRF acts in the brain to exacerbate acute liver injury through the sympathetic-noradrenergic pathways.

Effect of intracisternal thyrotropin-releasing hormone on hepatic blood flow in rats

Central neuropeptides play a role in many physiological regulatory processes through the autonomic nervous system. Thyrotropin-releasing hormone (TRH) is distributed in the central nervous system and acts as a neurotransmitter to regulate gastric functions through vagal-muscarinic pathways. The central effect of the TRH analog on hepatic blood flow was investigated in urethan-anesthetized rats. Hepatic blood flow was determined by the hydrogen gas clearance technique. Intracisternal injection of the stable TRH analog RX-77368 (5-100 ng) dose dependently increased hepatic blood flow with peak response at 15 min after the peptide was administered (net change from basal for vehicle and 5, 10, 100, and 500 ng RX-77368 was 2.0 +/- 0.2, 8.9 +/- 0.8, 19.4 +/- 2.6, 32.6 +/- 3.3, and 28.5 +/- 6.8 ml.min-1.100 g-1, respectively), and this stimulatory effect returned to baseline at 90 min. The stimulation of hepatic blood flow by the intracisternally administered TRH analog was abolished by atropine methyl nitrate (0.15 mg/kg ip), indomethacin (5 mg/kg ip), NG-nitro-L-arginine methyl ester (10 mg/kg iv), and hepatic branch vagotomy but not by cervical spinal cord transection (C6 level). Intravenous injection of RX-77368 did not have any effect on hepatic blood flow. These results indicate that TRH acts in the central nervous system to stimulate hepatic blood flow through vagal-muscarinic and indomethacin- and nitric oxide-dependent pathways.Central neuropeptides play a role in many physiological regulatory processes through the autonomic nervous system. Thyrotropin-releasing hormone (TRH) is distributed in the central nervous system and acts as a neurotransmitter to regulate gastric functions through vagal-muscarinic pathways. The central effect of the TRH analog on hepatic blood flow was investigated in urethan-anesthetized rats. Hepatic blood flow was determined by the hydrogen gas clearance technique. Intracisternal injection of the stable TRH analog RX-77368 (5-100 ng) dose dependently increased hepatic blood flow with peak response at 15 min after the peptide was administered (net change from basal for vehicle and 5, 10, 100, and 500 ng RX-77368 was 2.0 ± 0.2, 8.9 ± 0.8, 19.4 ± 2.6, 32.6 ± 3.3, and 28.5 ± 6.8 ml ⋅ min-1 ⋅ 100 g-1, respectively), and this stimulatory effect returned to baseline at 90 min. The stimulation of hepatic blood flow by the intracisternally administered TRH analog was abolished by atropine methyl nitrate (0.15 mg/kg ip), indomethacin (5 mg/kg ip), N G-nitro-l-arginine methyl ester (10 mg/kg iv), and hepatic branch vagotomy but not by cervical spinal cord transection (C6 level). Intravenous injection of RX-77368 did not have any effect on hepatic blood flow. These results indicate that TRH acts in the central nervous system to stimulate hepatic blood flow through vagal-muscarinic and indomethacin- and nitric oxide-dependent pathways.

Neuropeptide Y in the dorsal vagal complex stimulates bicarbonate- dependent bile secretion in rats

BACKGROUND & AIMS Central administration of neuropeptide Y (NPY) enhances bile secretion through vagal pathways in animal models. NPY nerve fibers and receptors are localized in the dorsal vagal complex (DVC), and retrograde tracing techniques have shown that hepatic vagal nerves are projected mainly from the left DVC. However, nothing is known about the central sites of action for NPY to elicit bile secretion. The medullary sites of the action for NPY were investigated in this study. METHODS The bile duct was cannulated in urethane-anesthetized and bile acid-compensated rats. After measuring basal secretion, NPY was microinjected into the DVC and bile response was observed for 100 minutes. Either left or right cervical vagotomy or hepatic branch vagotomy was performed 2 hours before the peptide. RESULTS Microinjection of NPY (7-30 pmol) into the left DVC, but not the right DVC, dose-dependently increased bile acid-independent and bicarbonate-dependent bile secretion. Stimulation of bile secretion by NPY was eliminated by left cervical and hepatic branch vagotomy but not by right cervical vagotomy. CONCLUSIONS NPY acts in the left DVC to stimulate bile acid-independent and bicarbonate-dependent bile secretion through the left cervical and hepatic vagus; these findings suggest that neuropeptides may act in the specific brain nuclei to regulate hepatic function.

Long-term effect of α-glucosidase inhibitor on late dumping syndrome

Dumping syndrome commonly occurs after gastrectomy. The late dumping, which is one of the dumping syndromes, is due to postprandial hypoglycaemia caused by an excessive insulin secretion after a sharp rise in plasma glucose. Several treatments, including operation, dietary fibre and somatostatin, have been attempted to relieve dumping symptoms. These treatments take effect through modulation of plasma insulin and glucose levels, but their efficacy is still under consideration. α‐Glucosidase inhibitor attenuates the postprandial increase of plasma glucose levels and is widely used for treatment of non‐insulin‐dependent diabetes mellitus (NIDDM). The acute effect of α‐glucosidase inhibitor on late dumping syndrome has been reported by some studies with test meals. The purpose of this study was to evaluate a long‐term effect of α‐glucosidase inhibitor treatment with ordinary meals in late dumping patients with NIDDM because administration of α‐glucosidase inhibitor is only ethically allowed for diabetic patients in Japan. Six late dumping patients with NIDDM were orally administered α‐glucosidase inhibitor, acarbose (50 or 100 mg), three times a day before each meal for 1 month. Diurnal changes of plasma glucose, insulin and pancreatic glucagon levels were compared before and after the α‐glucosidase inhibitor treatment. All patients had late dumping‐related symptoms, such as weakness, palpitation and dizziness before the induction of α‐glucosidase inhibitor treatment. Patients suffered from a rapid fall in plasma glucose levels from hyperglycaemia at the same time as dumping symptoms. These late dumping‐related symptoms disappeared and a rapid change of plasma glucose and insulin levels were attenuated after the α‐glucosidase inhibitor treatment. These data suggest a long‐term therapeutic efficacy of α‐glucosidase inhibitor for late dumping patients.

Central neuropeptide Y enhances bile secretion through vagal and muscarinic but not nitric oxide pathways in rats

Neuropeptide Y (NPY) acts in the central nervous system to regulate gastrointestinal functions in rats and dogs. The effects of intracisternal injection of NPY on bile secretion and biliary components were investigated in urethane-anesthetized rats with bile duct cannula. Intracisternal NPY (0.02-0.12 nmol) dose-dependently increased bile secretion by 9.2-19.5%. The secretory response occurred within the first 20-40 min and lasted for the 120-min observation period. Intravenous injection of NPY (0.12 nmol) did not modify bile secretion under identical conditions. Biliary bile acid, phospholipid, and cholesterol secretion were not modified by intracisternal injection of NPY (0.12 nmol), whereas bicarbonate was increased by 19.0 +/- 1.7% from 40 to 120 min after NPY injection. Cervical cord transection at the C6 level, acute bilateral adrenalectomy (-120 min), or injection of NG-nitro-L-arginine methyl ester (10 mg/kg, IV, -15 min), an inhibitor of nitric oxide biosynthesis, did not alter intracisternal NPY (0.12 nmol)-induced stimulation of bile secretion. Atropine (2.0 mg/kg, IP, -30 min) and bilateral cervical vagotomy (-120 min) completely abolished the stimulatory effect of intracisternal NPY (0.12 nmol) on bile secretion. These findings indicate that NPY acts in the brain to stimulate bicarbonate-dependent bile secretion through vagal and muscarinic pathways and suggest that peptides in the central nervous system may be involved in the vagal regulation of bile secretion.