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The role of nerve growth factor and p75 neurotrophin receptor in recovery from liver fibrosis

The role of nerve growth factor and p75 neurotrophin receptor in recovery from liver fibrosis
The role of nerve growth factor and p75 neurotrophin receptor in recovery from liver fibrosis
Rodent hepatic myofibroblasts are susceptible to nerve growth factor-mediated apoptosis through p75 neurotrophin receptor ligation. Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. I show that human hepatic myofibroblasts exhibit differential responses to mature and pro-nerve growth factor/p75 neurotrophin receptor-mediated signals. Whilst mature nerve growth factor is proapoptotic, pronerve growth factor protects human hepatic myofibroblasts from serum-deprivation and cycloheximide-induced apoptosis. To define the dominant effect of p75 neurotrophin receptor-mediated events in experimental liver fibrosis I have used a mouse lacking the p75 neurotrophin receptor ligand-binding domain but expressing the intracellular domain. I show that absence of p75 neurotrophin receptor ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75 neurotrophin receptor limits hepatocyte proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Moreover, in recovery from experimental liver fibrosis the fall in pro-nerve growth factor mirrors loss of hepatic myofibroblasts by apoptosis. Thus, nerve growth factor species have a differential effect on hepatic myofibroblast survival, and p75 neurotrophin receptor ligand-mediated events facilitate reduction of liver fibrosis via regulation of hepatic myofibroblast proliferation and apoptosis, and hepatocyte proliferation.
Kendall, Timothy J.
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Kendall, Timothy J.
9417bf7e-408d-469a-9604-28e333f9adbf
Iredale, John
db99ade5-cefc-4712-ba93-cf09c27288d8
Benyon, Chris
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Kendall, Timothy J. (2008) The role of nerve growth factor and p75 neurotrophin receptor in recovery from liver fibrosis. University of Southampton, School of Medicine, Doctoral Thesis, 255pp.

Record type: Thesis (Doctoral)

Abstract

Rodent hepatic myofibroblasts are susceptible to nerve growth factor-mediated apoptosis through p75 neurotrophin receptor ligation. Hepatic myofibroblast apoptosis is critical to resolution of liver fibrosis. I show that human hepatic myofibroblasts exhibit differential responses to mature and pro-nerve growth factor/p75 neurotrophin receptor-mediated signals. Whilst mature nerve growth factor is proapoptotic, pronerve growth factor protects human hepatic myofibroblasts from serum-deprivation and cycloheximide-induced apoptosis. To define the dominant effect of p75 neurotrophin receptor-mediated events in experimental liver fibrosis I have used a mouse lacking the p75 neurotrophin receptor ligand-binding domain but expressing the intracellular domain. I show that absence of p75 neurotrophin receptor ligand-mediated signals leads to significantly retarded architectural resolution and reduced hepatic myofibroblast loss by apoptosis. Lack of the ligand-competent p75 neurotrophin receptor limits hepatocyte proliferative capacity in vivo without preventing hepatic stellate cell transdifferentiation. Moreover, in recovery from experimental liver fibrosis the fall in pro-nerve growth factor mirrors loss of hepatic myofibroblasts by apoptosis. Thus, nerve growth factor species have a differential effect on hepatic myofibroblast survival, and p75 neurotrophin receptor ligand-mediated events facilitate reduction of liver fibrosis via regulation of hepatic myofibroblast proliferation and apoptosis, and hepatocyte proliferation.

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Published date: 12 November 2008
Organisations: University of Southampton

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Local EPrints ID: 161479
URI: http://eprints.soton.ac.uk/id/eprint/161479
PURE UUID: 72bb96fc-a0d7-4739-8148-0fa701609af4

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Date deposited: 16 Aug 2010 14:03
Last modified: 14 Mar 2024 02:00

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Contributors

Author: Timothy J. Kendall
Thesis advisor: John Iredale
Thesis advisor: Chris Benyon

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