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|Title: ||Molecular mechanisms of hepatic injury and repair|
|Authors: ||Henderson, Neil C|
|Supervisor(s): ||Sethi, Tariq|
|Issue Date: ||Jun-2007|
|Publisher: ||The University of Edinburgh. College of Medicine and Veterinary Medicine. School of Clinical Sciences and Community Health|
|Abstract: ||In this thesis I examined molecular mechanisms involved in acute and chronic liver
injury, and also studied basic pathways mediating tumour promotion.
Acute hepatic failure secondary to paracetamol poisoning is associated with high
mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen activated
protein kinase family and is a key intracellular signaling molecule involved in the control
of cell fate. Paracetamol induced hepatic JNK activation in both human and murine
paracetamol hepatotoxicity, and in a murine model preceded the onset of hepatocyte
death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of
action) markedly reduced mortality in murine paracetamol hepatotoxicity. In addition,
delayed administration of JNK inhibitor was more effective than N-acetylcysteine
following paracetamol poisoning in mice. JNK inhibition was not protective in acute
carbon tetrachloride or anti-Fas antibody mediated hepatic injury, suggesting specificity
for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or
JNK2 genes did not protect against paracetamol-induced hepatic damage.
Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly
inhibited hepatic TNF-alpha production following paracetamol poisoning. These data
demonstrate a central role for JNK in the pathogenesis of paracetamol induced liver
failure, thereby identifying JNK as an important therapeutic target in the treatment of
Liver fibrosis with loss of tissue architecture and subsequent hepatic failure represents a
massive healthcare burden worldwide. Expression of Galectin-3 (a beta-galactoside binding
animal lectin) is upregulated in established human fibrotic liver disease, during the
development of experimental liver fibrosis and is temporally and spatially related to the
induction and resolution of experimental hepatic fibrosis. Disruption of the gene
encoding Galectin-3 blocks transdifferentiation of precursors to myofibroblasts in vitro
and in vivo, markedly attenuating hepatic scarring in a murine model of liver fibrosis.
Inhibition of Galectin-3 expression by siRNA in primary murine and human hepatic stellate cells significantly reduced myofibroblast activation and procollagen(I) expression.
The reduction in hepatic fibrosis observed in the Galectin-3-/- mouse occurred despite
equivalent liver injury and inflammation, and similar tissue expression of TGF-beta. TGF-beta
failed to transactivate Galectin-3-/- hepatic stellate cells, in contrast with wild type hepatic
stellate cells. However TGF-beta stimulated signaling via Smad-2 and 3 was equivalent in
both Galectin-3-/- and wild type hepatic stellate cells indicating that Galectin-3 is required
for TGF-beta mediated myofibroblast activation and matrix production. This supports a
novel and important mechanistic role for Galectin-3 in the regulation of myofibroblast
activation and consequent liver fibrosis. Finally, in vivo siRNA knockdown of Galectin-3
inhibited myofibroblast activation following hepatic injury and may therefore provide a
novel therapeutic approach to the prevention and treatment of liver fibrosis.
CD98hc (a ligand for Galectin-3) constitutively and specifically associates with beta1
integrins and is highly expressed on the surface of human tumour cells irrespective of the
tissue of origin. CD98hc promotes both anchorage- and serum-independent growth.
Using chimeras of CD98hc and the type II membrane protein CD69 demonstrated that
the transmembrane domain of CD98hc is necessary and sufficient for integrin association
in cells. Furthermore, CD98hc/β1 integrin association is required for focal adhesion
kinase-dependent phosphoinositol 3-hydroxykinase activation and cellular transformation.
Amino acids 82-87 in the putative cytoplasmic/transmembrane region appear to be
critical for the oncogenic potential of CD98hc and provide a novel mechanism for tumour
promotion by integrins.|
|Appears in Collections:||School of Clinical Sciences thesis and dissertation collection|
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