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Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury

Lookup NU author(s): Dr Karen Wallace, Professor Matthew Wright

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Abstract

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 α-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 anti-fibrogenic therapy, supporting a role for liver monocytes and/or macrophages in the promotion of liver fibrosis reduction. © 2008 European Association for the Study of the Liver.

Publication metadata

Author(s): Douglass A, Wallace K, Parr R, Park J, Durward E, Broadbent I, Barelle C, Porter A, Wright MC

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2008

Volume: 49

Issue: 1

Pages: 88-98

Print publication date: 01/07/2008

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.jhep.2008.01.032

DOI: 10.1016/j.jhep.2008.01.032

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