Thrombin Inhibits the Migration of Human Liver Myofibroblasts
Identifieur interne : 004444 ( Istex/Corpus ); précédent : 004443; suivant : 004445Thrombin Inhibits the Migration of Human Liver Myofibroblasts
Auteurs : J. Gillibert-Duplantier ; V. Neaud ; A. Desmoulière ; P. Bioulac-Sage ; J. RosenbaumSource :
- Wound Repair and Regeneration [ 1067-1927 ] ; 2005-01.
Abstract
Liver myofibroblasts are the key cells of liver fibrogenesis. Recent data show that the serine proteinase thrombin is involved in fibrogenesis through a mitogenic effect on myofibroblasts. The aim of this study was to evaluate the effects of thrombin on the migration of human liver myofibroblasts; another major parameter in fibrogenesis. In a Boyden chamber assay, thrombin dose‐dependently (10−10–10−7 M) decreased spontaneous myofibroblast migration down to 49 ± 1% of control values (p = 5.10−10) without affecting cell adhesion or viability. Thrombin effect was blocked by its specific catalytic inhibitor hirudin and could be reproduced by using the proteinase‐activated receptor‐1 (PAR‐1) agonist SFLLRNP. Thrombin also completely inhibited migration when induced by the chemotactic agent platelet‐derived growth factor‐BB. We then investigated the signaling mechanisms involved. The COX‐2 inhibitor NS398 dose‐dependently (2.5–10 μM) blunted the inhibitory effect of thrombin on spontaneous migration. However, NS398 did not reverse the inhibitory effect of thrombin on PDGF‐BB‐induced migration. Phosphatidylinositol 3‐kinase (PI3‐K) is a major determinant of chemotaxis induced by PDGF. Whereas thrombin did not itself induce PI3‐K activity, as shown by the lack of detectable phosphorylation of Akt‐1, it inhibited PDGF‐BB‐induced Akt‐1 phosphorylation. This effect was dependent of the Rho/ROCK pathway since it was abolished in the presence of the ROCK inhibitor Y‐27632. In summary, thrombin, acting via a proteinase‐activated receptor, inhibits human liver myofibroblasts migration. Inhibition of basal migration is dependent on COX‐2, while inhibition of PDGF‐BB‐induced migration involves decreased PI3‐K activation via a Rho/ROCK mechanism. We suggest that thrombin could thus stabilize activated myofibroblasts on the site of active fibrogenesis.
Url:
DOI: 10.1111/j.1067-1927.2005.130117j.x
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Gillibert-Duplantier</name><affiliation><mods:affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Neaud, V" sort="Neaud, V" uniqKey="Neaud V" first="V" last="Neaud">V. Neaud</name><affiliation><mods:affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Desmouliere, A" sort="Desmouliere, A" uniqKey="Desmouliere A" first="A" last="Desmoulière">A. Desmoulière</name><affiliation><mods:affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation></author><author><name sortKey="Bioulac Age, P" sort="Bioulac Age, P" uniqKey="Bioulac Age P" first="P" last="Bioulac-Sage">P. 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Rosenbaum</name><affiliation><mods:affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Wound Repair and Regeneration</title><title level="j" type="alt">WOUND REPAIR REGENERATION</title><idno type="ISSN">1067-1927</idno><idno type="eISSN">1524-475X</idno><imprint><biblScope unit="vol">13</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="A19">A19</biblScope><biblScope unit="page" to="A19">A19</biblScope><biblScope unit="page-count">1</biblScope><publisher>Blackwell Science Inc</publisher><pubPlace>Oxford, UK; Malden, USA</pubPlace><date type="published" when="2005-01">2005-01</date></imprint><idno type="ISSN">1067-1927</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1067-1927</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Liver myofibroblasts are the key cells of liver fibrogenesis. Recent data show that the serine proteinase thrombin is involved in fibrogenesis through a mitogenic effect on myofibroblasts. The aim of this study was to evaluate the effects of thrombin on the migration of human liver myofibroblasts; another major parameter in fibrogenesis. In a Boyden chamber assay, thrombin dose‐dependently (10−10–10−7 M) decreased spontaneous myofibroblast migration down to 49 ± 1% of control values (p = 5.10−10) without affecting cell adhesion or viability. Thrombin effect was blocked by its specific catalytic inhibitor hirudin and could be reproduced by using the proteinase‐activated receptor‐1 (PAR‐1) agonist SFLLRNP. Thrombin also completely inhibited migration when induced by the chemotactic agent platelet‐derived growth factor‐BB. We then investigated the signaling mechanisms involved. The COX‐2 inhibitor NS398 dose‐dependently (2.5–10 μM) blunted the inhibitory effect of thrombin on spontaneous migration. However, NS398 did not reverse the inhibitory effect of thrombin on PDGF‐BB‐induced migration. Phosphatidylinositol 3‐kinase (PI3‐K) is a major determinant of chemotaxis induced by PDGF. Whereas thrombin did not itself induce PI3‐K activity, as shown by the lack of detectable phosphorylation of Akt‐1, it inhibited PDGF‐BB‐induced Akt‐1 phosphorylation. This effect was dependent of the Rho/ROCK pathway since it was abolished in the presence of the ROCK inhibitor Y‐27632. In summary, thrombin, acting via a proteinase‐activated receptor, inhibits human liver myofibroblasts migration. Inhibition of basal migration is dependent on COX‐2, while inhibition of PDGF‐BB‐induced migration involves decreased PI3‐K activation via a Rho/ROCK mechanism. 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Gillibert‐Duplantier</name><affiliations><json:string>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>V Neaud</name><affiliations><json:string>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>A Desmoulière</name><affiliations><json:string>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>P Bioulac‐Sage</name><affiliations><json:string>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item><json:item><name>J Rosenbaum</name><affiliations><json:string>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</json:string></affiliations></json:item></author><articleId><json:string>WRR130117J</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>abstract</json:string></originalGenre><abstract>Liver myofibroblasts are the key cells of liver fibrogenesis. Recent data show that the serine proteinase thrombin is involved in fibrogenesis through a mitogenic effect on myofibroblasts. The aim of this study was to evaluate the effects of thrombin on the migration of human liver myofibroblasts; another major parameter in fibrogenesis. In a Boyden chamber assay, thrombin dose‐dependently (10−10–10−7 M) decreased spontaneous myofibroblast migration down to 49 ± 1% of control values (p = 5.10−10) without affecting cell adhesion or viability. Thrombin effect was blocked by its specific catalytic inhibitor hirudin and could be reproduced by using the proteinase‐activated receptor‐1 (PAR‐1) agonist SFLLRNP. Thrombin also completely inhibited migration when induced by the chemotactic agent platelet‐derived growth factor‐BB. We then investigated the signaling mechanisms involved. The COX‐2 inhibitor NS398 dose‐dependently (2.5–10 μM) blunted the inhibitory effect of thrombin on spontaneous migration. However, NS398 did not reverse the inhibitory effect of thrombin on PDGF‐BB‐induced migration. Phosphatidylinositol 3‐kinase (PI3‐K) is a major determinant of chemotaxis induced by PDGF. Whereas thrombin did not itself induce PI3‐K activity, as shown by the lack of detectable phosphorylation of Akt‐1, it inhibited PDGF‐BB‐induced Akt‐1 phosphorylation. This effect was dependent of the Rho/ROCK pathway since it was abolished in the presence of the ROCK inhibitor Y‐27632. In summary, thrombin, acting via a proteinase‐activated receptor, inhibits human liver myofibroblasts migration. Inhibition of basal migration is dependent on COX‐2, while inhibition of PDGF‐BB‐induced migration involves decreased PI3‐K activation via a Rho/ROCK mechanism. We suggest that thrombin could thus stabilize activated myofibroblasts on the site of active fibrogenesis.</abstract><qualityIndicators><score>8.5</score><pdfVersion>1.4</pdfVersion><pdfPageSize>595 x 782 pts</pdfPageSize><refBibsNative>false</refBibsNative><abstractCharCount>1866</abstractCharCount><pdfWordCount>8613</pdfWordCount><pdfCharCount>55105</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>256</abstractWordCount></qualityIndicators><title>Thrombin Inhibits the Migration of Human Liver Myofibroblasts</title><genre><json:string>abstract</json:string></genre><host><title>Wound Repair and Regeneration</title><language><json:string>unknown</json:string></language><doi><json:string>10.1111/(ISSN)1524-475X</json:string></doi><issn><json:string>1067-1927</json:string></issn><eissn><json:string>1524-475X</json:string></eissn><publisherId><json:string>WRR</json:string></publisherId><volume>13</volume><issue>1</issue><pages><first>A19</first><last>A19</last><total>1</total></pages><genre><json:string>journal</json:string></genre></host><categories><wos><json:string>science</json:string><json:string>surgery</json:string><json:string>medicine, research & experimental</json:string><json:string>dermatology</json:string><json:string>cell biology</json:string></wos><scienceMetrix><json:string>health sciences</json:string><json:string>clinical medicine</json:string><json:string>dermatology & venereal diseases</json:string></scienceMetrix><inist><json:string>sciences appliquees, technologies et medecines</json:string><json:string>sciences biologiques et medicales</json:string><json:string>sciences medicales</json:string></inist></categories><publicationDate>2005</publicationDate><copyrightDate>2005</copyrightDate><doi><json:string>10.1111/j.1067-1927.2005.130117j.x</json:string></doi><id>9108CE187D09E7FB1B34C5534B0D7C0B35E9B989</id><score>1</score><fulltext><json:item><extension>pdf</extension><original>true</original><mimetype>application/pdf</mimetype><uri>https://api.istex.fr/document/9108CE187D09E7FB1B34C5534B0D7C0B35E9B989/fulltext/pdf</uri></json:item><json:item><extension>zip</extension><original>false</original><mimetype>application/zip</mimetype><uri>https://api.istex.fr/document/9108CE187D09E7FB1B34C5534B0D7C0B35E9B989/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/9108CE187D09E7FB1B34C5534B0D7C0B35E9B989/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main">Thrombin Inhibits the Migration of Human Liver Myofibroblasts</title></titleStmt><publicationStmt><publisher>Blackwell Science Inc</publisher><pubPlace>Oxford, UK; Malden, USA</pubPlace><date type="published" when="2005-01"></date></publicationStmt><notesStmt><note type="content-type" subtype="abstract" source="abstract" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-HPN7T1Q2-R">abstract</note><note type="publication-type" subtype="journal" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="abstract"><analytic><title level="a" type="main">Thrombin Inhibits the Migration of Human Liver Myofibroblasts</title><author xml:id="author-0000"><persName><forename type="first">J</forename><surname>Gillibert‐Duplantier</surname></persName><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">V</forename><surname>Neaud</surname></persName><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0002"><persName><forename type="first">A</forename><surname>Desmoulière</surname></persName><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0003"><persName><forename type="first">P</forename><surname>Bioulac‐Sage</surname></persName><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France<address><country key="FR"></country></address></affiliation></author><author xml:id="author-0004"><persName><forename type="first">J</forename><surname>Rosenbaum</surname></persName><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France<address><country key="FR"></country></address></affiliation></author><idno type="istex">9108CE187D09E7FB1B34C5534B0D7C0B35E9B989</idno><idno type="DOI">10.1111/j.1067-1927.2005.130117j.x</idno><idno type="unit">WRR130117J</idno><idno type="toTypesetVersion">file:WRR.WRR130117J.pdf</idno></analytic><monogr><title level="j" type="main">Wound Repair and Regeneration</title><title level="j" type="alt">WOUND REPAIR REGENERATION</title><idno type="pISSN">1067-1927</idno><idno type="eISSN">1524-475X</idno><idno type="book-DOI">10.1111/(ISSN)1524-475X</idno><idno type="book-part-DOI">10.1111/wrr.2005.13.issue-1</idno><idno type="product">WRR</idno><idno type="publisherDivision">ST</idno><imprint><biblScope unit="vol">13</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="A19">A19</biblScope><biblScope unit="page" to="A19">A19</biblScope><biblScope unit="page-count">1</biblScope><publisher>Blackwell Science Inc</publisher><pubPlace>Oxford, UK; Malden, USA</pubPlace><date type="published" when="2005-01"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract xml:lang="en" style="main"><p>Liver myofibroblasts are the key cells of liver fibrogenesis. Recent data show that the serine proteinase thrombin is involved in fibrogenesis through a mitogenic effect on myofibroblasts. The aim of this study was to evaluate the effects of thrombin on the migration of human liver myofibroblasts; another major parameter in fibrogenesis.</p><p>In a Boyden chamber assay, thrombin dose‐dependently (10<hi rend="superscript">−10</hi>–10<hi rend="superscript">−7</hi> M) decreased spontaneous myofibroblast migration down to 49 ± 1% of control values (p = 5.10<hi rend="superscript">−10</hi>) without affecting cell adhesion or viability. Thrombin effect was blocked by its specific catalytic inhibitor hirudin and could be reproduced by using the proteinase‐activated receptor‐1 (PAR‐1) agonist SFLLRNP. Thrombin also completely inhibited migration when induced by the chemotactic agent platelet‐derived growth factor‐BB. We then investigated the signaling mechanisms involved. The COX‐2 inhibitor NS398 dose‐dependently (2.5–10 μM) blunted the inhibitory effect of thrombin on spontaneous migration. However, NS398 did not reverse the inhibitory effect of thrombin on PDGF‐BB‐induced migration. Phosphatidylinositol 3‐kinase (PI3‐K) is a major determinant of chemotaxis induced by PDGF. Whereas thrombin did not itself induce PI3‐K activity, as shown by the lack of detectable phosphorylation of Akt‐1, it inhibited PDGF‐BB‐induced Akt‐1 phosphorylation. This effect was dependent of the Rho/ROCK pathway since it was abolished in the presence of the ROCK inhibitor Y‐27632.</p><p>In summary, thrombin, acting via a proteinase‐activated receptor, inhibits human liver myofibroblasts migration. Inhibition of basal migration is dependent on COX‐2, while inhibition of PDGF‐BB‐induced migration involves decreased PI3‐K activation via a Rho/ROCK mechanism. We suggest that thrombin could thus stabilize activated myofibroblasts on the site of active fibrogenesis.</p></abstract><textClass><classCode scheme="tocHeading1">Abstracts ‐ European Tissue Repair Society Focus Meeting</classCode></textClass><langUsage><language ident="EN"></language></langUsage></profileDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/9108CE187D09E7FB1B34C5534B0D7C0B35E9B989/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley component found"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Science Inc</publisherName><publisherLoc>Oxford, UK; Malden, USA</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1524-475X</doi><issn type="print">1067-1927</issn><issn type="electronic">1524-475X</issn><idGroup><id type="product" value="WRR"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="WOUND REPAIR REGENERATION">Wound Repair and Regeneration</title></titleGroup></publicationMeta><publicationMeta level="part" position="01101"><doi origin="wiley">10.1111/wrr.2005.13.issue-1</doi><numberingGroup><numbering type="journalVolume" number="13">13</numbering><numbering type="journalIssue" number="1">1</numbering></numberingGroup><coverDate startDate="2005-01">January 2005</coverDate></publicationMeta><publicationMeta level="unit" type="abstract" position="0001900" status="forIssue"><doi origin="wiley">10.1111/j.1067-1927.2005.130117j.x</doi><idGroup><id type="unit" value="WRR130117J"></id></idGroup><countGroup><count type="pageTotal" number="1"></count></countGroup><titleGroup><title type="tocHeading1">Abstracts ‐ European Tissue Repair Society Focus Meeting</title></titleGroup><eventGroup><event type="firstOnline" date="2005-01-17"></event><event type="publishedOnlineFinalForm" date="2005-01-17"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.17 mode:FullText" date="2010-09-08"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2014-02-10"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-11-04"></event></eventGroup><numberingGroup><numbering type="pageFirst">A19</numbering><numbering type="pageLast">A19</numbering></numberingGroup><linkGroup><link type="toTypesetVersion" href="file:WRR.WRR130117J.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="0"></count><count type="tableTotal" number="0"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="0"></count><count type="wordTotal" number="4249"></count><count type="linksPubMed" number="0"></count><count type="linksCrossRef" number="0"></count></countGroup><titleGroup><title type="main">Thrombin Inhibits the Migration of Human Liver Myofibroblasts</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><givenNames>J</givenNames><familyName>Gillibert‐Duplantier</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1"><personName><givenNames>V</givenNames><familyName>Neaud</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1"><personName><givenNames>A</givenNames><familyName>Desmoulière</familyName></personName></creator><creator creatorRole="author" xml:id="cr4" affiliationRef="#a1"><personName><givenNames>P</givenNames><familyName>Bioulac‐Sage</familyName></personName></creator><creator creatorRole="author" xml:id="cr5" affiliationRef="#a1"><personName><givenNames>J</givenNames><familyName>Rosenbaum</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="FR"><unparsedAffiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</unparsedAffiliation></affiliation></affiliationGroup><abstractGroup><abstract type="main" xml:lang="en"><p>Liver myofibroblasts are the key cells of liver fibrogenesis. Recent data show that the serine proteinase thrombin is involved in fibrogenesis through a mitogenic effect on myofibroblasts. The aim of this study was to evaluate the effects of thrombin on the migration of human liver myofibroblasts; another major parameter in fibrogenesis.</p><p>In a Boyden chamber assay, thrombin dose‐dependently (10<sup>−10</sup>–10<sup>−7</sup> M) decreased spontaneous myofibroblast migration down to 49 ± 1% of control values (p = 5.10<sup>−10</sup>) without affecting cell adhesion or viability. Thrombin effect was blocked by its specific catalytic inhibitor hirudin and could be reproduced by using the proteinase‐activated receptor‐1 (PAR‐1) agonist SFLLRNP. Thrombin also completely inhibited migration when induced by the chemotactic agent platelet‐derived growth factor‐BB. We then investigated the signaling mechanisms involved. The COX‐2 inhibitor NS398 dose‐dependently (2.5–10 μM) blunted the inhibitory effect of thrombin on spontaneous migration. However, NS398 did not reverse the inhibitory effect of thrombin on PDGF‐BB‐induced migration. Phosphatidylinositol 3‐kinase (PI3‐K) is a major determinant of chemotaxis induced by PDGF. Whereas thrombin did not itself induce PI3‐K activity, as shown by the lack of detectable phosphorylation of Akt‐1, it inhibited PDGF‐BB‐induced Akt‐1 phosphorylation. This effect was dependent of the Rho/ROCK pathway since it was abolished in the presence of the ROCK inhibitor Y‐27632.</p><p>In summary, thrombin, acting via a proteinase‐activated receptor, inhibits human liver myofibroblasts migration. Inhibition of basal migration is dependent on COX‐2, while inhibition of PDGF‐BB‐induced migration involves decreased PI3‐K activation via a Rho/ROCK mechanism. We suggest that thrombin could thus stabilize activated myofibroblasts on the site of active fibrogenesis.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Thrombin Inhibits the Migration of Human Liver Myofibroblasts</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Thrombin Inhibits the Migration of Human Liver Myofibroblasts</title></titleInfo><name type="personal"><namePart type="given">J</namePart><namePart type="family">Gillibert‐Duplantier</namePart><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">V</namePart><namePart type="family">Neaud</namePart><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A</namePart><namePart type="family">Desmoulière</namePart><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">P</namePart><namePart type="family">Bioulac‐Sage</namePart><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">J</namePart><namePart type="family">Rosenbaum</namePart><affiliation>GREF, INSERM E0362, Université Victor Segalen Bordeaux 2, Bordeaux, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="abstract" displayLabel="abstract"></genre><originInfo><publisher>Blackwell Science Inc</publisher><place><placeTerm type="text">Oxford, UK; Malden, USA</placeTerm></place><dateIssued encoding="w3cdtf">2005-01</dateIssued><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="words">4249</extent></physicalDescription><abstract lang="en">Liver myofibroblasts are the key cells of liver fibrogenesis. Recent data show that the serine proteinase thrombin is involved in fibrogenesis through a mitogenic effect on myofibroblasts. The aim of this study was to evaluate the effects of thrombin on the migration of human liver myofibroblasts; another major parameter in fibrogenesis. In a Boyden chamber assay, thrombin dose‐dependently (10−10–10−7 M) decreased spontaneous myofibroblast migration down to 49 ± 1% of control values (p = 5.10−10) without affecting cell adhesion or viability. Thrombin effect was blocked by its specific catalytic inhibitor hirudin and could be reproduced by using the proteinase‐activated receptor‐1 (PAR‐1) agonist SFLLRNP. Thrombin also completely inhibited migration when induced by the chemotactic agent platelet‐derived growth factor‐BB. We then investigated the signaling mechanisms involved. The COX‐2 inhibitor NS398 dose‐dependently (2.5–10 μM) blunted the inhibitory effect of thrombin on spontaneous migration. However, NS398 did not reverse the inhibitory effect of thrombin on PDGF‐BB‐induced migration. Phosphatidylinositol 3‐kinase (PI3‐K) is a major determinant of chemotaxis induced by PDGF. Whereas thrombin did not itself induce PI3‐K activity, as shown by the lack of detectable phosphorylation of Akt‐1, it inhibited PDGF‐BB‐induced Akt‐1 phosphorylation. This effect was dependent of the Rho/ROCK pathway since it was abolished in the presence of the ROCK inhibitor Y‐27632. In summary, thrombin, acting via a proteinase‐activated receptor, inhibits human liver myofibroblasts migration. Inhibition of basal migration is dependent on COX‐2, while inhibition of PDGF‐BB‐induced migration involves decreased PI3‐K activation via a Rho/ROCK mechanism. We suggest that thrombin could thus stabilize activated myofibroblasts on the site of active fibrogenesis.</abstract><relatedItem type="host"><titleInfo><title>Wound Repair and Regeneration</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">1067-1927</identifier><identifier type="eISSN">1524-475X</identifier><identifier type="DOI">10.1111/(ISSN)1524-475X</identifier><identifier type="PublisherID">WRR</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>13</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>A19</start><end>A19</end><total>1</total></extent></part></relatedItem><identifier type="istex">9108CE187D09E7FB1B34C5534B0D7C0B35E9B989</identifier><identifier type="DOI">10.1111/j.1067-1927.2005.130117j.x</identifier><identifier type="ArticleID">WRR130117J</identifier><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Science Inc</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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