Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis
| Autor: | Gakuhei Son, Laura W. Schrum, Richard A. Rippe, Ian N. Hines, Jeff Lindquist |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Liver Cirrhosis
Mice Transgenic Biology Collagen Type I Article Adenoviridae Extracellular matrix Mice Phosphatidylinositol 3-Kinases Fibrosis Cell Movement medicine Hepatic Stellate Cells Animals Cyclin D1 Protein kinase B Cells Cultured Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Mice Inbred BALB C Hepatology Ribosomal Protein S6 Kinases 70-kDa Transforming growth factor beta medicine.disease Actins Cell biology Extracellular Matrix Disease Models Animal Biochemistry biology.protein Hepatic stellate cell Disease Progression Phosphatidylinositol 3-kinase signaling Signal transduction Hepatic fibrosis Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Hepatology (Baltimore, Md.). 50(5) |
| ISSN: | 1527-3350 |
| Popis: | The hepatic stellate cell (HSC) is the primary cell type in the liver responsible for excess collagen deposition during fibrosis. Following a fibrogenic stimulus the cell changes from a quiescent vitamin A–storing cell to an activated cell type associated with increased extracellular matrix synthesis and increased cell proliferation. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been shown to regulate several aspects of HSC activation in vitro, including collagen synthesis and cell proliferation. Using a targeted approach to inhibit PI3K signaling specifically in HSCs, we investigated the role of PI3K in HSCs using a rodent model of hepatic fibrosis. An adenovirus expressing a dominant negative form of PI3K under control of the smooth muscle α-actin (αSMA) promoter was generated (Ad-SMAdnPI3K). Transducing HSCs with Ad-SMAdnPI3K resulted in decreased proliferation, migration, collagen expression, and several additional profibrogenic genes, while also promoting cell death. Inhibition of PI3K signaling was also associated with reduced activation of Akt, p70 S6 kinase, and extracellular regulated kinase signaling as well as reduced cyclin D1 expression. Administering Ad-SMAdnPI3K to mice following bile duct ligation resulted in reduced HSC activation and decreased extracellular matrix deposition, including collagen expression. A reduction in profibrogenic mediators, including transforming growth factor beta, tissue inhibitor of metalloproteinase 1, and connective tissue growth factor was also noted. However, liver damage, assessed by alanine aminotransferase levels, was not reduced. Conclusion: Inhibition of PI3K signaling in HSCs during active fibrogenesis inhibits extracellular matrix deposition, including synthesis of type I collagen, and reduces expression of profibrogenic factors. These data suggest that targeting PI3K signaling in HSCs may represent an effective therapeutic target for hepatic fibrosis. (Hepatology 2009.) |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text