15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Chemical-and-Drug-Induced-Liver-Injury

Sinusoidal obstruction syndrome (SOS) is a major complication of chemotherapy and hematopoietic stem cell transplantation. The early stage of SOS is characterized by liver sinusoidal endothelial cell (LSEC) injury accompanied by platelet aggregation. Thromboxane A

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cells, Cultured; Chemical and Drug Induced Liver Injury; Endothelial Cells; Male; Mice, Inbred C57BL; Mice, Knockout; Monocrotaline; Receptors, Thromboxane; Signal Transduction

It is thought that thromboxane A(2) (TxA(2)) contributes to the progression of inflammation during acute hepatic injury; however, it is still unknown whether TxA(2) is involved in liver repair. The objective of the present study was to examine the role of TxA(2) receptor (TP) signaling in liver injury and repair in response to toxic injury. Carbon tetrachloride (CCl(4)) was used to induce liver injury in TP knockout (TP(-/-)) mice and wild-type (WT) mice. In WT mice, serum levels of alanine aminotransferase (ALT) and the size of the necrotic area peaked at 24 and 48h, respectively, and then declined. In TP(-/-) mice, the changes in ALT levels were similar to WT mice, but liver regeneration was impaired as evidenced by remained elevated levels of hepatic necrosis and by delayed hepatocyte proliferation, which was associated with the reduced expression of growth factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and hepatocyte growth factor (HGF). In TP(-/-) mice, the accumulation of hepatic CD11b(+)/F4/80(+) macrophages in injured livers was attenuated, and the hepatic expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, the C-C chemokine receptor (CCR2), was reduced compared to WT. Additionally, the application of the TP receptor agonist, U-46619, enhanced the expression of MCP-1/CCL2 and CCR2 in peritoneal macrophages, which was associated with increased levels of IL-6, TNFα and HGF. These results suggested that TP receptor signaling facilitates liver recovery following CCl(4)-induced hepatotoxicity by affecting the expression of hepatotrophic growth factors, and through the recruitment of macrophages mediated by MCP-1/CCL2-CCR2 expression.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Carbon Tetrachloride; Cell Proliferation; Chemical and Drug Induced Liver Injury; Chemokine CCL2; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Hepatocyte Growth Factor; Hepatocytes; Interleukin-6; Liver; Liver Regeneration; Macrophages; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction; Receptors, CCR2; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Tumor Necrosis Factor-alpha

The role of thromboxane A2 (TxA2) in CCl4-induced liver disease was investigated in mice. Significant elevation of TxB2 in the liver was observed 6 hours after the injection of CCl4. Administration of OKY-046, a selective TxA2 synthetase inhibitor (10 and 50 mg/kg) and ONO-3708, a TxA2 receptor antagonist, (0.5, 1 and 2 mg/Kg) suppressed the elevation of serum GOT and GPT levels and histopathological changes of the liver. In addition, OKY-046 inhibited the elevation of TxB2 in the liver. When U-46619, a stable TxA2 mimetic was injected i.v. into the mice, clear elevation of serum GOT and GPT levels and histopathological score of the liver were observed. These results suggest that TxA2 play a role for the onset of CCl4-induced liver injury in mice.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Alanine Transaminase; Animals; Aspartate Aminotransferases; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Liver; Male; Methacrylates; Mice; Mice, Inbred Strains; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase