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The role of bile acids, adrenomedullin and salusins in mediating the hyperdynamic circulation syndrome and treatment of fibrogenesis in chronic liver disease

English title The role of bile acids, adrenomedullin and salusins in mediating the hyperdynamic circulation syndrome and treatment of fibrogenesis in chronic liver disease
Applicant Reichen Jürg
Number 105601
Funding scheme Project funding
Research institution Institut für Klinische Pharmakologie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Clinical Pharmacology
Start/End 01.10.2004 - 30.09.2007
Approved amount 296'000.00
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Keywords (6)

Portal hypertension; liver cirrhosis; bile acids; adrenomedullin; endothelin; salusin

Lay Summary (English)

Lead
Lay summary
Cirrhosis of the liver is due to a wound healing process leading to fibrosis (scarring)and portal hypertension (elevated pressure in the portal vein leading to ascites and internal bleeding). In humans the most frequent causes of cirrhosis are viral hepatitis, overweight and alcohol.Liver cirrhosis is the 8th leading cause of death in industrialized countries. Currently, the only treatment is liver transplantation which can be offered only to a minority of patients. The aim of our research is to better understand the role of different mediators in this process and thereby to develop new forms of treatment.
The studies are performed in rat models of cirrhosis, namely biliary cirrhosis induced by bile duct ligation and micronodular cirrhosis induced by chronic treatment with thioacetamide. PDGF (platelet derived growthfactor) has long been identified as one of first cytokines in inducing fibrosis by activating hepatic stellate cells (the main producers of collagen). Down-stream, PDGF signalling is mediated by mTOR (the mammalian target of Rapamycin).
We could demonstrate that treatment of cirrhotic rats with imatinib, an inhibitor of the PDGF-receptor kinase, inhibited the evolution of fibrosis but not its progression once cirrhosis was fully established (pdf:http://www.ikp.unibe.ch/lab2/neef2006a.pdf). In contrast, rapamycin - the classical inhibitor of mTOR - was effective in both preventing and treating fibrosis (pdf: http://www.ikp.unibe.ch/lab2/neef2006b.pdf).
Other potential treatment strategies include blocking G-protein coupled receptors such as those for endothelin or angiotensin II. This approach, either as monotherapy or in combination with rapamycin, was ineffective in our hands, though.
The promising results using rapamycin as an antifibrotic agent suggests that this agent or its congener, everolimus be studied in patients with advanced fibrosis of the liver.

Further research results: http://www.ikp.unibe.ch/lab2/lab2.html

Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
63476 The role of endothelin, its receptors and the isoenzymes of nitric oxide in portal hypertension 01.04.2001 Project funding
117725 Liver fibrosis: targetting mTOR, ras and different G-proteins in man and rat 01.10.2007 Project funding

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