Showing papers by "John P. Iredale published in 2006"
TL;DR: In vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.
Abstract: Central to fibrogenesis and the scarring of organs is the activation of fibroblasts into matrix-secreting myofibroblasts. We demonstrate that Galectin-3 expression is up-regulated in established human fibrotic liver disease and is temporally and spatially related to the induction and resolution of experimental hepatic fibrosis. Disruption of the Galectin-3 gene blocks myofibroblast activation and procollagen (I) expression in vitro and in vivo, markedly attenuating liver fibrosis. Addition of exogenous recombinant Galectin-3 in vitro reversed this abnormality. The reduction in hepatic fibrosis observed in the Galectin-3−/− mouse occurred despite equivalent liver injury and inflammation, and similar tissue expression of TGF-β. TGF-β failed to transactivate Galectin-3−/− hepatic stellate cells, in contrast with WT hepatic stellate cells; however, TGF-β-stimulated Smad-2 and -3 activation was equivalent. These data suggest that Galectin-3 is required for TGF-β mediated myofibroblast activation and matrix production. Finally, in vivo siRNA knockdown of Galectin-3 inhibited myofibroblast activation after hepatic injury and may therefore provide an alternative therapeutic approach to the prevention and treatment of liver fibrosis.
535 citations
TL;DR: The BM contributes functionally and significantly to liver fibrosis and is a potential therapeutic target in Liver fibrosis, which should be vigilant for the possibility of enhanced organ fibrosis.
474 citations
TL;DR: Liver fibrosis has been shown to be a bidirectional process and increasing data from laboratory and clinical studies reveal that even advanced fibrosis and cirrhosis are potentially reversible.
Abstract: Liver fibrosis occurs as a result of a wide range of injurious processes and in its end-stage results in cirrhosis. This gross disruption of liver architecture is associated with impaired hepatic func
60 citations
TL;DR: The reversal of liver fibrosis is not a new phenomenon, but new approaches to promote resolution of fibrosis are being built on the foundations that were provided by research into the basic mechanisms of fibrogenesis.
53 citations
TL;DR: In this article, the role of pericellular collagen I proteolysis in both regulating proliferation and maintaining the activated myofibroblastic phenotype of stellate cells in vitro was investigated.
44 citations
01 Jan 2006
TL;DR: Recovery from acute and chronic injury is characterized by apoptosis of the TIMP expressing HSCs thereby relieving the inhibition of matrix degradation and regulating HSC apoptosis in progressive injury and counterbalances cell proliferation.
Abstract: Liver injury is associated with activation of hepatic stellate cells (HSC) to a myofibroblast-like phenotype. In cirrhotic liver injury, activated HSCs are the major source of fibrillar collagens, an excess of which characterise fibrotic matrix. HSCs also have the capacity to remodel this matrix as they express matrix metalloproteinases (MMPs) and their specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Recovery from acute and chronic injury is characterized by apoptosis of the TIMP expressing HSCs thereby relieving the inhibition of matrix degradation. HSC apoptosis is regulated in progressive injury and counterbalances cell proliferation. Apoptosis probably also represents a default pathway for the HSCs resulting from the withdrawal of survival signals after cessation of injury. The survival of activated HSCs in liver injury is dependent on soluble growth factors and cytokines, and on compontents of the fibrotic matrix itself. Additionally, stimulation of death domain receptors expressed on HSCs can precipitate their apoptosis.
2 citations