How can transforming growth factor beta be targeted usefully to combat liver fibrosis?
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.
Shek
Fanny W
FW
Liver and Pancreatic Research Group, University Division of Infection, Inflammation and Repair, Southampton General Hospital, Southampton, UK.
Benyon
R Christopher
RC
D000818:Animals; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D051381:Rats; D013853:Thioacetamide; D016212:Transforming Growth Factor beta / Q000502:physiology*; D053773:Transforming Growth Factor beta1
C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013853:Thioacetamide; D020782:Matrix Metalloproteinases