Pentoxifylline blocks hepatic stellate cell activation independently of phosphodiesterase inhibitory activity
| Autor: | K Houglum, Kwan Sik Lee, Dennis A. Carson, Howard B. Cottam, Mario Chojkier, D B Wasson |
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| Rok vydání: | 1997 |
| Předmět: |
Male
medicine.medical_specialty Phosphodiesterase Inhibitors Physiology Liver cytology Biology 3T3 cells Pentoxifylline Rats Sprague-Dawley Mice Proto-Oncogene Proteins c-myb In vivo Proto-Oncogene Proteins Physiology (medical) Internal medicine Gene expression Cyclic AMP medicine Animals Phosphorylation Cyclic AMP Response Element-Binding Protein Promoter Regions Genetic Carbon Tetrachloride Cell Nucleus Hepatology NF-kappa B Gastroenterology Phosphodiesterase 3T3 Cells Hepatic stellate cell activation Actins Rats Cell biology Oxidative Stress medicine.anatomical_structure Endocrinology Gene Expression Regulation Liver Trans-Activators Hepatic stellate cell Collagen Cell Division medicine.drug |
| Zdroj: | American Journal of Physiology-Gastrointestinal and Liver Physiology. 273:G1094-G1100 |
| ISSN: | 1522-1547 0193-1857 |
| Popis: | Activated, but not quiescent, hepatic stellate cells (lipocytes) have a high level of collagen type I and smooth muscle actin (SMA) gene expression. Therefore, stellate cell activation is a critical step in hepatic fibrosis. The mechanisms leading to stellate cell activation in vivo are unknown. The characteristic hepatic oxidative stress cascade induced in rats by CCl4markedly stimulated stellate cell entry into S phase, nuclear factor (NF)-κB activity, and c- myb expression. These changes were prevented by pentoxifylline, which also decreased CCl4-induced hepatic injury. As expected, cAMP-mediated phosphorylation of CREB-Ser133was induced in vivo in stellate cells by pentoxifylline but not by its metabolite 5, an N-1 carboxypropyl derivative, which lacks phosphodiesterase inhibitory activity. Stellate cell nuclear extracts from CCl4-treated, but not from control, animals formed a complex with the critical promoter E box of the α-SMA gene, which was disrupted by c- myb antibodies and competed with by c- myb cognate DNA. Treatment with pentoxifylline or metabolite 5 prevented the molecular abnormalities characteristic of stellate cell activation induced by CCl4. These results suggest that induction of c- myb plays an important role in the in vivo activation of stellate cells. Pentoxifylline blocks stellate cell activation in vivo independently of its inhibitory effects on phosphodiesterases by interfering with the oxidative stress cascade and the activation of NF-κB and c- myb. |
| Databáze: | OpenAIRE |
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