beraprost and Liver-Diseases

Studies of the molecular and cellular mechanisms of concanavalin A (ConA)-induced liver injury have provided important knowledge on the pathogenesis of many liver diseases involving hepatic inflammation. However, studies identifying hepato-protective factors based on the mechanistic understanding of this model are lacking. Evidence suggests that certain prostaglandin (PG) products of cyclooxygenase (COX)-1 and COX-2 provide important anti-inflammatory and cytoprotective functions in some pathophysiological states. In the present study, we demonstrate a protective role of COX-2 derived PGs in ConA-induced liver injury. COX-2(-/-) mice developed much more severe liver damage upon ConA treatment compared with wild-type and COX-1(-/-) mice. Treatment of COX-2(-/-) mice with misoprostol (a PGE(1/2) analog) or beraprost (a PGI(2) analog) significantly decreased ConA-induced liver injury. Data from both in vivo and in vitro experiments demonstrated that misoprostol and beraprost acted directly on hepatic leukocytes, including natural killer (NK)T and T cells, and down-regulated their production of interferon (IFN)-gamma, which are critical in mediating ConA-induced tissue damage. Collectively, the results provide strong evidence that the protective effects of COX-2 within the liver are mediated through the production of PGE(2) and PGI(2), which exert anti-inflammatory functions. These findings suggest that COX-2-derived PGs may have great therapeutic potentials in treating patients with inflammatory liver diseases.

Topics: Animals; Chemical and Drug Induced Liver Injury; Concanavalin A; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Down-Regulation; Epoprostenol; Gene Expression Regulation; Gene Expression Regulation, Enzymologic; Inflammation; Interferon-gamma; Liver Diseases; Male; Mice; Mice, Knockout; Misoprostol; Mitogens

We reported earlier that reactive oxygen species are implicated in necrotic injury induced by a transient exposure of cultured renal tubular cells to a high concentration of cisplatin but not in apoptosis occurring after continuous exposure to a low concentration of cisplatin. We report here the protective effect of cyclic AMP against cisplatin-induced necrosis in cultured renal tubular cells as well as cisplatin-induced acute renal failure in rats. Several pharmacological agents that stimulate cyclic AMP signaling, including the nonhydrolyzable cyclic AMP analogue dibutyryl cyclic AMP, forskolin, 3-isobutyl-1-methylxanthine, and a prostacyclin analogue, beraprost, prevented cisplatin-induced cell injury in a protein kinase A-dependent manner. Cisplatin enhanced lipid peroxidation, decreased CuZn superoxide dismutase (SOD) while enhancing MnSOD activity, and increased cellular tumor necrosis factor-alpha (TNF-alpha) content. The elevation of TNF-alpha content and cell injury induced by cisplatin were attenuated by p38 mitogen-activated protein kinase (MAPK) inhibitors including SB203580 and PD169316. Indeed, cisplatin increased the number of phosphorylated p38 MAPK-like immunoreactive cells. These intracellular events were all reversed by antioxidants such as N-acetylcysteine (NAC) and glutathione or cyclic AMP analogues. The in vivo acute renal injury after cisplatin injection was associated with the elevation of renal TNF-alpha content. The cisplatin-induced renal injury and the increase in TNF-alpha content were reversed by NAC or beraprost. These findings suggest that cyclic AMP protects renal tubular cells against cisplatin-induced oxidative injury by obliterating reactive oxygen species and subsequent inhibition of TNF-alpha synthesis through blockade of p38 MAPK activation.

Topics: Acetylcysteine; Animals; Antineoplastic Agents; Antioxidants; Apoptosis; Chemical and Drug Induced Liver Injury; Cisplatin; Cyclic AMP; Enzyme Activation; Enzyme Inhibitors; Epoprostenol; Fluorescent Antibody Technique; In Situ Nick-End Labeling; Lipid Peroxidation; Liver Diseases; Male; p38 Mitogen-Activated Protein Kinases; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Endothelial cell damage causes massive hepatic necrosis as a result of fibrin deposition in the hepatic sinusoids. When a stable analog of prostaglandin I2, beraprost sodium, was administered to rats given either dimethylnitrosamine, carbon tetrachloride, or endotoxin following Corynebacterium parvum administration, the hepatic necrosis produced in each was attenuated, but to a greater extent in the dimethylnitrosamine and endotoxin/Corynebacterium parvum models, where fibrin deposition in the hepatic sinusoids occurs, as compared to the carbon tetrachloride model, where such fibrin deposition does not occur. Beraprost sodium reduced the expected increase of portal venous pressure in the endotoxin/Corynebacterium parvum model without affecting plasma thrombin-antithrombin III complex levels. Beraprost sodium also significantly reduced cell killing of both isolated rat hepatocytes and hepatic sinusoidal endothelial cells exposed to tert-butyl hydroperoxide when compared to controls. Beraprost sodium could prove to be a therapeutic candidate for the treatment of hepatic necrosis, particularly in cases associated with fibrin deposition in the hepatic sinusoids because of its fibrin clot-clearing action.

Topics: Animals; Antithrombin III; Capillaries; Carbon Tetrachloride; Cells, Cultured; Dimethylnitrosamine; Endothelium, Vascular; Endotoxins; Epoprostenol; Fibrin; Liver; Liver Diseases; Male; Necrosis; Peptide Hydrolases; Portal Pressure; Propionibacterium acnes; Prothrombin Time; Rats; Rats, Inbred F344