Novel anti‐fibrotic modalities for liver fibrosis: molecular targeting and regenerative medicine in fibrosis therapy

Y Inagaki, R Higashiyama… - … of gastroenterology and …, 2012 - Wiley Online Library
Y Inagaki, R Higashiyama, K Higashi
Journal of gastroenterology and hepatology, 2012Wiley Online Library
Based on the cellular and molecular mechanisms underlying hepatic fibrogenesis, several
kinds of approaches have been proposed to treat liver fibrosis. Among a number of growth
factors and cytokines that regulate collagen metabolism, transforming growth factor (TGF)‐β
is the most potent factor to accelerate liver fibrosis by activating hepatic stellate cells,
stimulating collagen gene transcription, and suppressing matrix metalloproteinases
expression. Thus, TGF‐β as well as its intracellular mediators, Smad proteins, can be …
Abstract
Based on the cellular and molecular mechanisms underlying hepatic fibrogenesis, several kinds of approaches have been proposed to treat liver fibrosis. Among a number of growth factors and cytokines that regulate collagen metabolism, transforming growth factor (TGF)‐β is the most potent factor to accelerate liver fibrosis by activating hepatic stellate cells, stimulating collagen gene transcription, and suppressing matrix metalloproteinases expression. Thus, TGF‐β as well as its intracellular mediators, Smad proteins, can be potential therapeutic targets for liver fibrosis. Constitutive phosphorylation and nuclear accumulation of Smad3 is the common feature of activated stellate cells. We have synthesized a novel small compound that inhibits Smad3‐dependent collagen gene transcription by promoting nuclear import of a transcriptional repressor, YB‐1. Another insight into anti‐fibrotic strategies is the contribution of bone marrow‐derived cells to the regression of liver fibrosis. Administration of granulocyte‐colony stimulating factor enhanced the migration of bone marrow‐derived cells into fibrotic liver tissue and accelerated the regression of experimental liver fibrosis. We have recently identified novel unknown factors expressed by bone marrow‐derived cells that not only ameliorate liver fibrosis but also accelerate regeneration of fibrotic liver.
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