How can transforming growth factor beta be targeted usefully to combat liver fibrosis?
- 1 February 2004
- journal article
- editorial
- Published by Wolters Kluwer Health in European Journal of Gastroenterology & Hepatology
- Vol. 16 (2) , 123-126
- https://doi.org/10.1097/00042737-200402000-00001
Abstract
Transforming growth factor beta-1 (TGF-beta 1) plays a pivotal role in tissue fibrogenesis. Understanding the factors that control resolution of fibrosis is critical to devising means to combat clinical fibrosis. Future challenges would include designing ways to block the fibrosis-specific actions of TGF-beta. Blockade of transforming growth factor beta (TGF-beta) activity in vivo in animal models has proven to be an effective means of inhibiting the fibrotic response to injury in various organs. Similarly, transgenic animals in which TGF-beta 1 expression is artificially enhanced show marked spontaneous fibrosis or increased fibrotic response to injury. TGF-beta is known to effect fibroplasias, not only by its well known action of increasing extracellular matrix synthesis but also by coordinately regulating key proteins which mediate connective tissue homeostasis. This includes down-regulation of interstitial collagenase and other matrix metalloproteinases and up-regulation of antiproteases such as tissue inhibitor of metalloproteinase I and plasminogen activator inhibitor. Whilst inhibition of TGF-beta activity appears to be well tolerated in rodents over several weeks, the ultimately lethal phenotype of TGF-beta 1 knockout mice warns us that this pluripotent cytokine is essential for normal health. Therefore, downstream pathways activated by TGF-beta, which might be specific for its fibrotic effects, might be more useful targets for human fibrotic disease therapy. For example, the TGF-beta response protein connective tissue growth factor may be a good target for antifibrotics but definitive evidence awaits development of suitable genetically modified animal models and specific inhibitors.Keywords
This publication has 16 references indexed in Scilit:
- Thioacetamide-induced hepatic fibrosis in transforming growth factor beta-1 transgenic miceEuropean Journal of Gastroenterology & Hepatology, 2004
- Conditional Tetracycline–Regulated Expression of Tgf–β1 in Liver of Transgenic Mice Leads to Reversible Intermediary FibrosisHepatology, 2003
- Hepatocellular expression of a dominant-negative mutant TGF-β type II receptor accelerates chemically induced hepatocarcinogenesisOncogene, 2001
- Connective tissue growth factor: an attractive therapeutic target in fibrotic renal diseaseEmerging Therapeutic Targets, 2001
- Prevention of rat hepatic fibrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-βGastroenterology, 2001
- Blockade of type β transforming growth factor signaling prevents liver fibrosis and dysfunction in the ratProceedings of the National Academy of Sciences, 1999
- Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-α and TGF-β1Journal of Hepatology, 1999
- Biology of TGF-β in knockout and transgenic mouse modelsKidney International, 1997
- Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.Proceedings of the National Academy of Sciences, 1995
- Thioacetamide-induced cirrhosis-like liver lesions in rats usefulness and reliability of this animal modelExperimental pathology, 1988