期刊
JOURNAL OF HEPATOLOGY
卷 49, 期 1, 页码 88-98出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2008.01.032
关键词
C1-3; drug targeting; gliotoxin; stellate; scAb; MMP-13; liver; fibrosis; myofibroblast
资金
- Biotechnology and Biological Sciences Research Council Funding Source: Medline
Background/Aims: Myofibroblast apoptosis promotes the resolution of liver fibrosis. However, retaining macrophages may enhance reversal. The effects of specifically stimulating myofibroblast apoptosis in vivo were assessed. Methods: A single chain antibody (C1-3) to an extracellular domain of a myofibroblast membrane protein was injected as a fluorescent- or gliotoxin conjugate into mice with liver fibrosis. Results: C1-3 specifically targeted alpha-smooth muscle actin positive liver myofibroblasts within scar regions of the liver in vivo and did not co-localise with liver monocytes/macrophages. Injection of free gliotoxin stimulated a 2-fold increase in non-parenchymal cell apoptosis and depleted liver myofibroblasts by 30% and monocytes/macrophages by 50% but had no effect on fibrosis severity in the sustained injury model employed. In contrast, C1-3-targeted gliotoxin stimulated a 5-fold increase in non-parenchymal cell apoptosis, depleted liver myofibroblasts by 60%, did not affect the number of monocytes/macrophages and significantly reduced fibrosis severity. Fibrosis reduction was associated with increased metalloproteinase-13 levels. Conclusions: These data demonstrate that specific targeting of liver myofibroblast apoptosis is the most effective antifibrogenic therapy, supporting a role for liver monocytes and/or macrophages in the promotion of liver fibrosis reduction. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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