dinoprost and Cholestasis

To investigate the therapeutic effect of glycyrrhizin arginine salt on rat cholestatic cirrhosis, we subjected male Sprague Dawley rats to common bile duct ligation for 14 days and treated them with distilled water (model group), arginine, or a low or high dose of glycyrrhizin arginine salt by gavage. A sham-operated group was used as a control group. Treatment with glycyrrhizin arginine salt substantially improved animal growth rates, reduced the ratio of liver weight to body weight and decreased total bilirubin, aspartate aminotransferase, 8-isoprostane and malondialdehyde compared with the values measured in the model group. The progress of liver fibrosis, as detected by hematoxylin and eosin and Masson's trichrome staining, was slower in the glycyrrhizin arginine salt groups than in the model group or the arginine group. Reductions of bile salt pool size, hepatic hydroxyproline content and fibrosis score were also seen in the glycyrrhizin arginine salt groups compared with the model group. Furthermore, glycyrrhizin arginine salt significantly reduced the expression of transforming growth factor [Formula: see text]1 (TGF-[Formula: see text]1), [Formula: see text]-smooth muscle actin, tumor necrosis factor-[Formula: see text] and matrix metalloproteinases 2 and 9. Glycyrrhizin arginine salt also inhibited the expression of [Formula: see text]-SMA and matrix metalloproteinases 2 and 9 in response to TGF-[Formula: see text]1 in LX-2 cells and primary rat hepatic stellate cells and mitigated the cytotoxicity induced by rat bile in HepG2 cells and primary rat hepatocytes.

Topics: Animals; Arginine; Aspartate Aminotransferases; Bilirubin; Cholestasis; Dinoprost; Drugs, Chinese Herbal; Glycyrrhizic Acid; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Male; Malondialdehyde; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta1

Parenteral nutrition-associated liver disease (PNALD) continues to cause morbidity and mortality for neonates with intestinal failure. Lipid peroxidation is one potential etiological factor. This study was designed to test if supplementing vitamin E into conventional soy-based lipid would reduce the risk of PNALD.. Sixteen piglets, aged 2-5 days and weighing 1.8-2.5 kg, were randomized to parenteral nutrition (PN) with soy lipid (SO, n = 8) or the same lipid plus α-tocopherol, the most bioactive form of vitamin E (SO+E, n = 8). After 17 days, bile flow, liver chemistry, gene expression associated with bile acid metabolism, and bile acid composition were assessed. C-reactive protein (CRP) and oxidative stress markers, including plasma 8-isoprostane, were measured. All results were compared with a sow-reared control group (CON).. Comparing PN-treated groups, SO vs SO+E mean bile flow (5.91 vs 5.54 µL/g liver; P = .83), serum bile acid concentration (39.2 vs 26.6 µmol/L; P = .12), and total bilirubin (35.2 vs 26.9 µmol/L; P = .56) were not different. Gene expression related to bile acid metabolism and bile composition was not different between PN groups. There was no difference in CRP (41.8 vs 36.8 µg/mL; P = .22) or in plasma 8-isoprostane (27.9 vs 26.1 pg/mL; P = .77).. In term neonatal piglets, supplemental vitamin E did not prevent cholestasis. Additional vitamin E was not associated with reduced inflammation or oxidative stress. The benefit of supplementing vitamin E into conventional lipid, vs adding fish oil, to prevent early onset of PNALD requires further clarification.

Topics: Alanine Transaminase; Alkaline Phosphatase; alpha-Tocopherol; Animals; Animals, Newborn; Bile Acids and Salts; Bilirubin; Biomarkers; C-Reactive Protein; Cholestasis; Dinoprost; Disease Models, Animal; Fat Emulsions, Intravenous; Female; gamma-Glutamyltransferase; Liver Diseases; Oxidative Stress; Parenteral Nutrition; Soybean Oil; Swine

Primary biliary cirrhosis (PBC) is a chronic cholestatic disorder characterised by an immunological, and often granulomatous, attack on bile ducts leading to fibrosis, cirrhosis, liver failure and death. Animal and human studies suggest that oxidant stress plays a key role in progression of other liver diseases, but no comprehensive investigation has been performed previously in PBC. A wide range of lipid peroxidation and antioxidant markers were measured in the blood and urine of 41 patients with histologically confirmed PBC. Lipid peroxidation markers were significantly elevated [plasma and urinary 8-isoprostane, P<0.001; plasma malondialdehyde (MDA), P=0.007] compared to age- and sex-matched controls. The most striking antioxidant depletion occurred with plasma total glutathione where levels were significantly reduced (30% of controls). Total serum antioxidant levels were decreased (P=0.013) and serum selenium and vitamin A were also lower (both P<0.001); vitamins C and E were normal. Most patients had early disease biochemically and were Child-Pugh grade A. Urinary 8-isoprostane correlated positively with Ludwig stage and markers of hepatic injury and cholestasis. This study clearly demonstrates that oxidant stress, as reflected in a comprehensive spectrum of lipid peroxidation and antioxidant markers, is a significant feature of early-stage PBC.

Topics: Antioxidants; Ascorbic Acid; Biomarkers; Cholestasis; Dinoprost; F2-Isoprostanes; Glutathione; Humans; Lipid Peroxidation; Liver; Liver Cirrhosis, Biliary; Malondialdehyde; Oxidants; Oxidative Stress; Selenium; Vitamin A; Vitamin E

Acute biliary obstruction is associated with the development of renal impairment and oxidative stress. The F2-isoprostanes, formed during oxidant injury, are renal vasoconstrictors acting via thromboxane (TX)-like receptors. We determined whether the formation of F2-isoprostanes is increased in experimental cholestasis and whether thiol containing antioxidants or ligands for the TXA2 receptor could improve renal function.. The effects on renal function of acute bile duct ligation (BDL) in the rat were studied for two days. The consequences of administration of N-acetylcysteine (NAC), alpha-lipoic acid (LA), the TX receptor antagonist (TXRA) BAYu3405, or placebo were then examined.. BDL caused a reduction in creatinine clearance from 1.10 +/- 0.05 to 0.55 +/- 0.05 ml/min and sodium excretion from 52 +/- 3 to 17 +/- 3 micromol/hr. Urinary F2-isoprostanes increased from 14 +/- 2 to 197 +/- 22 pg/ml following BDL. Renal functional changes were ameliorated by NAC (creatinine clearance 0.73 +/- 0.05 ml/min), LA (0.64 +/- 0.03 ml/min), and a TXRA (0.90 +/- 0.15 ml/min); P < 0.05. Similarly, sodium excretion was increased from 17 +/- 3 micromol/hr (placebo) to 34 +/- 3 micromol/hr (NAC), 29 +/- 3 micromol/hr (LA), and 38 +/- 5 micromol/hr (TXRA); P < 0.005. Hepatic glutathione concentrations increased from 6.5 +/- 0.3 micromol/g (normal liver) to 8.8 +/- 0.5 micromol/g (NAC) and 7.7 +/- 0.3 micromol/g (LA), P < 0.01. However, only LA markedly inhibited F2-isoprostane formation (197 +/- 22 to 36 +/- 11 pg/ml creatinine clearance; P < 0.05). Urinary TXB2 excretion was elevated after BDL (2.2 +/- 0.5 to 111.1 +/- 20.3 pg/min) but was unaffected by NAC and LA.. NAC, LA, and TXRA can partially prevent renal dysfunction in experimental cholestasis. The effects of the antioxidants are independent of their ability to inhibit lipid peroxidation or TX synthesis.

Topics: Acetylcysteine; Acute Kidney Injury; Animals; Antioxidants; Carbazoles; Cholestasis; Dinoprost; Glutathione; Ligands; Lipid Peroxidation; Male; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sodium; Sulfonamides; Thioctic Acid; Thromboxane B2

Bile secretion has been reported to be regulated by circulating hormones and by autonomic liver nerves. In the in situ perfused rat liver, prostaglandins reduce bile flow and bile acid secretion. The aim of this study was to investigate the regulation of bile secretion by prostaglandins in the in vivo situation. The bile duct and portal vein of anaesthetised Wistar rats were cannulated by polyethylene tubes. Bile flow was determined gravimetrically. Bile acids were quantified by the 3-alpha-hydroxy-steroid-dehydrogenase method and by high-pressure-liquid-chromatography (HPLC) separation. Administration of 1 microM prostaglandin F2 alpha into the portal vein over 5 minutes reduced bile flow from 1.57 microliter/min.g liver to 0.95 microliter/min.g liver and bile acids secretion from 148 to 81 nmol/100g/min. The administration of different doses (0.1 microM, 1 microM, 10 microM) of prostaglandin F2 alpha reduced hepatic bile secretion in a dose-dependent manner. Similar effects were observed after infusion of prostaglandin D2. However, the ratio of the bile acids (alpha-tauromuricholic acid), beta-tauromuricholic acid, taurocholic acid, taurochenodeoxycholic acid, and taurodeoxycholic acid) was unchanged by prostaglandin F2 alpha. In conclusion, infusion of prostaglandin F2 alpha into the portal vein results in a reduction of bile flow and bile acid secretion in a dose-dependent manner. These results suggest that the effect is linked to canicular bile secretion.

Topics: Animals; Bile; Bile Acids and Salts; Cholestasis; Dinoprost; Infusions, Intravenous; Kinetics; Male; Portal Vein; Prostaglandin D2; Rats; Rats, Wistar

A complete regulatory loop exists between the immune and neuroendocrine systems. Proinflammatory mediators such as endotoxin (lipopolysaccharide) and interleukin-1 (IL-1) are capable of activating the hypothalamic-pituitary-adrenal (HPA) axis at the hypothalamic level, presumably by inducing the synthesis of prostaglandins. We have recently identified abnormalities in the stress-induced activation of the HPA axis in cholestatic rats. Therefore, in rats with cholestasis due to bile duct resection and sham-resected controls, we studied alterations in proinflammatory mediator-induced activation of the HPA axis and documented the role of alterations in hypothalamic prostaglandin synthesis in these abnormalities. Systemic administration of endotoxin and IL-1 resulted in a significant attenuation of adrenocorticotropic hormone (ACTH) release into plasma in bile duct-resected compared with sham-resected animals. This suppression of endotoxin- or IL-1-induced ACTH release in bile duct-resected rats was associated with a complete absence of IL-1-induced hypothalamic release of prostaglandin E2 (PGE2) in vitro in these animals. In contrast, sham-resected rats exhibited a 70% increase in hypothalamic PGE2 secretion in vitro in response to IL-1. However, bile duct-resected rats exhibited HPA axis activation similar to that of sham-resected animals in response to intracerebroventricularly infused PGE2. Therefore, cholestasis in the rat is associated with an attenuation of central activation of the HPA axis by proinflammatory mediators that appears to be mediated, at least in part, by defective IL-1-induced hypothalamic prostaglandin production.

Topics: Adrenocorticotropic Hormone; Animals; Bile Ducts; Brain; Cholestasis; Dinoprost; Dinoprostone; Endotoxins; Hypothalamus; Interleukin-1; Male; Rats; Rats, Sprague-Dawley