Document Detail


The molecular mechanism of cholestatic pruritus.
MedLine Citation:
PMID:  21691108     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pruritus is a frequent symptom in patients with cholestatic liver diseases. Pruritus can be excruciating and, in rare cases, become a primary indication for liver transplantation. The molecular mechanism of itch signal transduction is largely unclear. It was our hypothesis that compounds which accumulate in the circulation during cholestasis act as direct or indirect pruritogens by affecting signaling in itch fibers. To test this, we screened plasma samples of a large group of patients with various cholestatic conditions for their capacity to activate neuroblastoma cells. Quite strikingly, we found that samples from itchy cholestatic patients caused a significantly higher activation than samples from non-itchy cholestatic patients and healthy controls. Purification revealed lysophosphatidic acid (LPA) as the active compound. LPA is a very potent signaling lipid that can activate cells through various LPA receptors. Subsequently, we could demonstrate that cholestatic patients with pruritus have highly elevated levels of serum autotaxin (ATX), the enzyme that converts lysophosphatidylcholine into LPA. This is a striking finding as ATX has never been connected to itch perception thus far. We have also shown that LPA, when injected intradermally, causes itching in mice. On the basis of our results, we hypothesize that during cholestasis, expression of ATX is induced and gives rise to increased local formation of LPA near unmyelinated nerve endings of itch fibers. LPA then activates these neurons through one of the LPA receptors, which in turn potentiates action potentials along itch fibers.
Authors:
Ronald P J Oude Elferink; Andreas E Kremer; Job J W W Martens; Ulrich H Beuers
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Publication Detail:
Type:  Journal Article     Date:  2011-06-17
Journal Detail:
Title:  Digestive diseases (Basel, Switzerland)     Volume:  29     ISSN:  1421-9875     ISO Abbreviation:  Dig Dis     Publication Date:  2011  
Date Detail:
Created Date:  2011-06-21     Completed Date:  2011-10-28     Revised Date:  2011-11-07    
Medline Journal Info:
Nlm Unique ID:  8701186     Medline TA:  Dig Dis     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  66-71     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 S. Karger AG, Basel.
Affiliation:
Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands. r.p.oude-elferink@amc.uva.nl
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MeSH Terms
Descriptor/Qualifier:
Animals
Calcium Signaling
Case-Control Studies
Cell Line, Tumor
Cholestasis / blood,  complications*,  metabolism*
Cholestasis, Intrahepatic / blood
Disease Models, Animal
Female
Humans
Lysophospholipids / metabolism
Mice
Multienzyme Complexes / blood
Phosphodiesterase I / blood
Pregnancy
Pregnancy Complications / blood
Pruritus / blood,  complications*,  metabolism*
Pyrophosphatases / blood
Chemical
Reg. No./Substance:
0/Lysophospholipids; 0/Multienzyme Complexes; 22002-87-5/lysophosphatidic acid; EC 3.1.4.1/Phosphodiesterase I; EC 3.1.4.39/alkylglycerophosphoethanolamine phosphodiesterase; EC 3.6.1.-/Pyrophosphatases

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