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.

These findings suggest that Con A induces TNF-alpha release, and this TNF-alpha stimulates MIP-2 induction, at least partially contributing to the liver injury mediated through the recruitment of neutrophils.

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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 (NPY), a 36-amino acid peptide, was first isolated from porcine brain and is the member of a family of structurally related peptides that includes peptide YY (PYY) and pancreatic polypeptide. 1,2 NPY is localized in the central nervous system, as well as the peripheral nervous system. 3 In the brain, NPY immunoreactive nerve fibers and terminals and NPY receptors are localized in the paraventricular nucleus of the hypothalamus and the dorsal vagal complex (DVC), including the dorsal motor nucleus of the vagus (DMN) and the nucleus of the solitary tract (NST), 4-6 which are important sites for the autonomic nervous regulation of gastrointestinal function. 7 Central administration of NPY affects several physiological functions. 8 With respect to the gastrointestinal system, central injection of NPY modifies gastric and pancreatic secretion in animal models. 9,10 Recently, Farouk et al. observed that intracerebroventricular injection of NPY stimulates bile acid-independent bile secretion through vagal pathways in rats and dogs, 11 and we have confirmed this effect by intracisternal injection of NPY in rats. 12 Moreover, we have found very recently that the left vagal complex is the specific brain site of action for NPY to induce bile stimulation. 13 It is now generally accepted on the basis of functional and ligand binding studies that NPY binds to and activates six different receptor subtypes, designated Y1, 2, 3, 4 (PP receptor), 5, and 6. 14-18 Y1 receptors exhibit similar affinity for NPY, PYY and [Leu 31 , Pro 34 ]NPY analog, and poor affinity for the C-terminal fragments of NPY/PYY, while Y2 receptors display affinity for NPY/PYY and C-terminal fragments of the peptides but not to the Y1 and 3 selective agonist, [Leu 31 , Pro 34 ]NPY. 14,19-23 PYY has been suggested to have high affinity for Y1 and 2 receptors, and less affinity for Y3 receptors. 14,20,24 Although Y1 receptors were suggested as postsynaptic and Y2 receptors as presynaptic, 25 later studies demonstrated that Y2 receptors are also localized presynaptically. 26 Both Y1 and Y2 receptors are localized in the DVC, 27 which has been identified as the specific brain site for NPY to stimulate bile secretion. 13 Peripherally released PYY binds to the DVC, 28 and microinjection of PYY into the DVC modified gastrointestinal functions. 29,30 The identity of the receptor subtype for NPY in the medulla that mediates the stimulation of bile acid-independent and bicarbonate-dependent bile secretion remains to be established. The present studies were performed to address this question by examining the effect of microinjection of NPY and NPY analogs into the DVC on bile secretion in rats. MATERIALS AND METHODS Animals.Male Wistar rats weighing 270 to 330 g (Charles River Japan Inc., Yokohama, Japan) were housed in group cages under conditions of controlled temperature (22-24°C) and illumination (12-hour light cycle starting at 8 AM) for at least 7 days before the experiments. Animals were maintained on laboratory chow and tap water. Experiments w...