In the fibrotic liver, hepatic stellate cells ( HSC) produce large amounts of collagen and secrete variety of mediators that promote development of fibrosis in this organ. Therefore, these cells are considered an attractive target for antifibrotic therapies. We incorporated the bioactive lipid dilinoleoylphosphatidylcholine ( DLPC) into the membrane of liposomes, and then we evaluated its effect on hepatic stellate cell activation and liver fibrosis. To target DLPC- liposomes to HSC, human serum albumin modified with mannose 6- phosphate ( M6P- HSA) was coupled to the surface of these liposomes. In vitro, the effects of the carrier were determined in primary cultures of HSC, Kupffer cells, and liver endothelial cells using real- time reverse transcription- polymerase chain reaction. In vivo DLPC- liposomes were tested in bile duct- ligated rats. Targeted M6PHSADLPC- liposomes and DLPC- liposomes significantly reduced gene expression levels for collagen 1 alpha 1, alpha-smooth muscle actin (alpha-SMA), and transforming growth factor-beta ( TGF-beta) in cultured HSC. In fibrotic livers, DLPC- liposomes decreased gene expression for TGF-beta and collagen 1 alpha 1 as well as alpha- SMA and collagen protein expression. In contrast, M6PHSADLPC- liposomes enhanced expression of profibrotic and proinflammatory genes in vivo. In cultured Kupffer and endothelial cells M6P- HSA liposomes influenced the expression of proinflammatory genes. Both types of liposomes increased hepatocyte glycogen content in fibrotic livers, indicating improved functionality of the hepatocytes. We conclude that DLPC- containing liposomes attenuate activation of cultured HSC. In fibrotic livers, M6P- HSA- mediated activation of Kupffer and endothelial cells probably counteracts this beneficial effect of DLPC- liposomes. Therefore, these bioactive drug carriers modulate the activity of all liver cells during liver fibrosis.
|Tijdschrift||Journal of Pharmacology and Experimental Therapeutics|
|Nummer van het tijdschrift||2|
|Status||Published - mei-2007|