15-deoxyprostaglandin-j2 and Liver-Cirrhosis

Delivery of apoptosis-inducing compounds to hepatic stellate cells (HSC) may be an effective strategy to reverse liver fibrosis. The aim of this study was therefore to examine the selective targeting of the apoptosis-inducing drug 15-deoxy-delta12,14-prostaglandin J2 (15dPGJ2) with two different HSC-carriers: human serum albumin modified with the sugar mannose-6-phosphate (M6PHSA) or albumin modified with PDGF-receptor recognizing peptides (pPBHSA).. After chemical conjugation of 15dPGJ2 to the carriers, the constructs displayed pharmacological activity and specific receptor-mediated binding to HSC in vitro. Unlike 15dPGJ2-pPBHSA, the cellular binding of 15dPGJ2-M6PHSA was reduced by a scavenger receptor antagonist. In vivo, both conjugates rapidly accumulated in fibrotic livers. Intrahepatic analysis revealed that 15dPGJ2-M6PHSA mainly accumulated in HSC, and to a lesser extent in Kupffer cells. 15dPGJ2-pPBHSA also predominantly accumulated in HSC with additional uptake in hepatocytes. Assessment of target receptors in human cirrhotic livers revealed that M6P/IGFII-receptor expression was present in fibrotic areas. PDGF-P receptor expression was abundantly expressed on human fibroblasts.. These studies show that 15dPGJ2 coupled to either M6PHSA or pPBHSA is specifically taken up by HSC and is highly effective within these cells. Both carriers differ with respect to receptor specificity, leading to differences in intrahepatic distribution. Nevertheless, both carriers can be used to deliver the apoptosis-inducing drug 15dPGJ2 to HSC in vivo.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Drug Delivery Systems; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; Liver; Liver Cirrhosis; Liver Cirrhosis, Experimental; Male; Mannosephosphates; Peptides; Prostaglandin D2; Rats; Rats, Wistar; Receptor, Platelet-Derived Growth Factor beta; Reproducibility of Results; Serum Albumin

Hepatic myofibroblasts are central in liver fibrogenesis associated with chronic liver diseases. We previously showed that heme-oxygenase-1 (HO-1) displays antifibrogenic properties in human hepatic myofibroblasts. Here, we further investigated the mechanisms regulating HO-1 expression.. Expression of HO-1 was assayed in cultured human hepatic myofibroblasts by Northern and Western blot. Functional studies were also performed in cultured human hepatic myofibroblasts.. 15-Deoxy-Delta(12,14)-prostaglandin J2 (15-d-PGJ2) elicited inhibition of proliferation and of alpha1(I) collagen mRNA expression. These effects were reproduced by the glutathione depletor diethyl maleate and blunted by the glutathione precursor N-acetyl cysteine, indicating the involvement of oxidative stress. Two consecutive events mediated inhibition of proliferation and of alpha1(I) collagen mRNA expression by 15-d-PGJ2: (i) mild oxidative stress characterized by a transient GSH decrease and (ii) activation of p38 MAPK, resulting in increased HO-1 mRNA stability.. Our results provide new insights into the regulatory mechanisms governing HO-1 expression in human hepatic myofibroblasts and identify mild oxidative stress and p38 MAPK as two consecutive early signals promoting HO-1 induction that are crucial for its antifibrogenic properties, namely inhibition of growth and extracellular matrix gene expression.

Topics: Cell Proliferation; Cells, Cultured; Collagen Type I; Enzyme Induction; Gene Expression; Heme Oxygenase (Decyclizing); Heme Oxygenase-1; Humans; Liver; Liver Cirrhosis; MAP Kinase Signaling System; Membrane Proteins; Oxidation-Reduction; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Prostaglandin D2; RNA Stability; RNA, Messenger