The alarmin HMGB‐1 influences healing outcomes in fetal skin wounds
Identifieur interne : 004F70 ( Istex/Corpus ); précédent : 004F69; suivant : 004F71The alarmin HMGB‐1 influences healing outcomes in fetal skin wounds
Auteurs : Adrienne D. Dardenne ; Brian C. Wulff ; Traci A. WilgusSource :
- Wound Repair and Regeneration [ 1067-1927 ] ; 2013-03.
Abstract
In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (HMGB‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, E18 keratinocytes expressed higher levels of HMGB‐1 compared with E15 keratinocytes. After injury, HMGB‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming E18 wounds, compared with scarless E15 wounds. Furthermore, instead of healing scarlessly, E15 wounds healed with scars when treated with HMGB‐1. HMGB‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. Together, these data suggest that extracellular HMGB‐1 levels influence the quality of healing in cutaneous wounds.
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DOI: 10.1111/wrr.12028
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">The alarmin HMGB‐1 influences healing outcomes in fetal skin wounds</title><author><name sortKey="Dardenne, Adrienne D" sort="Dardenne, Adrienne D" uniqKey="Dardenne A" first="Adrienne D." last="Dardenne">Adrienne D. Dardenne</name><affiliation><mods:affiliation>Department of Veterinary Preventive Medicine, University Laboratory Animal Resources, The Ohio State University, Ohio, Columbus</mods:affiliation></affiliation></author><author><name sortKey="Wulff, Brian C" sort="Wulff, Brian C" uniqKey="Wulff B" first="Brian C." last="Wulff">Brian C. Wulff</name><affiliation><mods:affiliation>Department of Pathology, The Ohio State University, Ohio, Columbus</mods:affiliation></affiliation></author><author><name sortKey="Wilgus, Traci A" sort="Wilgus, Traci A" uniqKey="Wilgus T" first="Traci A." last="Wilgus">Traci A. Wilgus</name><affiliation><mods:affiliation>Department of Pathology, The Ohio State University, Ohio, Columbus</mods:affiliation></affiliation><affiliation><mods:affiliation>Dr. Traci A. Wilgus, PhD, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.Tel: 614 366‐8526;Fax: 614 366‐9389;Email:</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: traci.wilgus@osumc.edu</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:A96DCA10748A4825D1C6355B871575F1BF94F146</idno><date when="2013" year="2013">2013</date><idno type="doi">10.1111/wrr.12028</idno><idno type="url">https://api.istex.fr/document/A96DCA10748A4825D1C6355B871575F1BF94F146/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">004F70</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">004F70</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">The alarmin <hi rend="fc">HMGB</hi>‐1 influences healing outcomes in fetal skin wounds</title><author><name sortKey="Dardenne, Adrienne D" sort="Dardenne, Adrienne D" uniqKey="Dardenne A" first="Adrienne D." last="Dardenne">Adrienne D. Dardenne</name><affiliation><mods:affiliation>Department of Veterinary Preventive Medicine, University Laboratory Animal Resources, The Ohio State University, Ohio, Columbus</mods:affiliation></affiliation></author><author><name sortKey="Wulff, Brian C" sort="Wulff, Brian C" uniqKey="Wulff B" first="Brian C." last="Wulff">Brian C. Wulff</name><affiliation><mods:affiliation>Department of Pathology, The Ohio State University, Ohio, Columbus</mods:affiliation></affiliation></author><author><name sortKey="Wilgus, Traci A" sort="Wilgus, Traci A" uniqKey="Wilgus T" first="Traci A." last="Wilgus">Traci A. Wilgus</name><affiliation><mods:affiliation>Department of Pathology, The Ohio State University, Ohio, Columbus</mods:affiliation></affiliation><affiliation><mods:affiliation>Dr. Traci A. Wilgus, PhD, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.Tel: 614 366‐8526;Fax: 614 366‐9389;Email:</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: traci.wilgus@osumc.edu</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 AND REGENERATION</title><idno type="ISSN">1067-1927</idno><idno type="eISSN">1524-475X</idno><imprint><biblScope unit="vol">21</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="282">282</biblScope><biblScope unit="page" to="291">291</biblScope><biblScope unit="page-count">10</biblScope><date type="published" when="2013-03">2013-03</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">In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (HMGB‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, E18 keratinocytes expressed higher levels of HMGB‐1 compared with E15 keratinocytes. After injury, HMGB‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming E18 wounds, compared with scarless E15 wounds. Furthermore, instead of healing scarlessly, E15 wounds healed with scars when treated with HMGB‐1. HMGB‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. 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Dardenne DVM, MS</name><affiliations><json:string>Department of Veterinary Preventive Medicine, University Laboratory Animal Resources, The Ohio State University, Ohio, Columbus</json:string></affiliations></json:item><json:item><name>Brian C. Wulff PhD</name><affiliations><json:string>Department of Pathology, The Ohio State University, Ohio, Columbus</json:string></affiliations></json:item><json:item><name>Traci A. Wilgus PhD</name><affiliations><json:string>Department of Pathology, The Ohio State University, Ohio, Columbus</json:string><json:string>Dr. Traci A. Wilgus, PhD, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.Tel: 614 366‐8526;Fax: 614 366‐9389;Email:</json:string><json:string>E-mail: traci.wilgus@osumc.edu</json:string></affiliations></json:item></author><articleId><json:string>WRR12028</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (HMGB‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, E18 keratinocytes expressed higher levels of HMGB‐1 compared with E15 keratinocytes. After injury, HMGB‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming E18 wounds, compared with scarless E15 wounds. Furthermore, instead of healing scarlessly, E15 wounds healed with scars when treated with HMGB‐1. HMGB‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. 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Wilgus, PhD, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA. Tel: 614 366‐8526; Fax: 614 366‐9389; Email: traci.wilgus@osumc.edu</affiliation></author><idno type="istex">A96DCA10748A4825D1C6355B871575F1BF94F146</idno><idno type="DOI">10.1111/wrr.12028</idno><idno type="unit">WRR12028</idno><idno type="toTypesetVersion">file:WRR.WRR12028.pdf</idno></analytic><monogr><title level="j" type="main">Wound Repair and Regeneration</title><title level="j" type="alt">WOUND REPAIR AND 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.2013.21.issue-2</idno><idno type="product">WRR</idno><imprint><biblScope unit="vol">21</biblScope><biblScope unit="issue">2</biblScope><biblScope unit="page" from="282">282</biblScope><biblScope unit="page" to="291">291</biblScope><biblScope unit="page-count">10</biblScope><date type="published" when="2013-03"></date></imprint></monogr></biblStruct></sourceDesc></fileDesc><profileDesc><abstract style="main"><head>Abstract</head><p>In mice, cutaneous wounds generated early in development (embryonic day 15, <hi rend="fc">E</hi>15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, <hi rend="fc">E</hi>18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (<hi rend="fc">HMGB</hi>‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, <hi rend="fc">E</hi>18 keratinocytes expressed higher levels of <hi rend="fc">HMGB</hi>‐1 compared with <hi rend="fc">E</hi>15 keratinocytes. After injury, <hi rend="fc">HMGB</hi>‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming <hi rend="fc">E</hi>18 wounds, compared with scarless <hi rend="fc">E</hi>15 wounds. Furthermore, instead of healing scarlessly, <hi rend="fc">E</hi>15 wounds healed with scars when treated with <hi rend="fc">HMGB</hi>‐1. <hi rend="fc">HMGB</hi>‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. Together, these data suggest that extracellular <hi rend="fc">HMGB</hi>‐1 levels influence the quality of healing in cutaneous wounds.</p></abstract><textClass><classCode scheme="tocHeading1">Original Research‐Basic Science</classCode><classCode scheme="articleCategory">Original Research‐Basic Science</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/A96DCA10748A4825D1C6355B871575F1BF94F146/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component type="serialArticle" version="2.0" xml:id="wrr12028" xml:lang="en"><header><publicationMeta level="product"><doi origin="wiley">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></idGroup><titleGroup><title sort="WOUND REPAIR AND REGENERATION" type="main">Wound Repair and Regeneration</title><title type="short">Wound Repair Regen</title></titleGroup></publicationMeta><publicationMeta level="part" position="03102"><doi>10.1111/wrr.2013.21.issue-2</doi><copyright ownership="thirdParty">© 2013 Wound Healing Society</copyright><numberingGroup><numbering number="21" type="journalVolume">21</numbering><numbering type="journalIssue">2</numbering></numberingGroup><coverDate startDate="2013-03">March‐April 2013</coverDate></publicationMeta><publicationMeta level="unit" position="120" status="forIssue" type="article"><doi>10.1111/wrr.12028</doi><idGroup><id type="unit" value="WRR12028"></id></idGroup><countGroup><count number="10" type="pageTotal"></count></countGroup><titleGroup><title type="tocHeading1">Original Research‐Basic Science</title><title type="articleCategory">Original Research‐Basic Science</title></titleGroup><copyright ownership="thirdParty">© 2013 by the Wound Healing Society</copyright><eventGroup><event agent="bestset" date="2013-01-14" type="xmlCreated"></event><event date="2012-07-12" type="manuscriptReceived"></event><event date="2012-12-25" type="manuscriptAccepted"></event><event type="publishedOnlineEarlyUnpaginated" date="2013-02-25"></event><event type="firstOnline" date="2013-02-25"></event><event type="publishedOnlineFinalForm" date="2013-03-06"></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:4.6.4 mode:FullText" date="2015-10-02"></event></eventGroup><numberingGroup><numbering type="pageFirst">282</numbering><numbering type="pageLast">291</numbering></numberingGroup><correspondenceTo><lineatedText><line><b>Reprint requests:</b></line><line>Dr. Traci A. Wilgus, PhD, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.</line><line>Tel: 614 366‐8526;</line><line>Fax: 614 366‐9389;</line><line>Email: <email>traci.wilgus@osumc.edu</email></line></lineatedText></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:WRR.WRR12028.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="short">HMGB‐1 and fetal wound healing</title><title type="shortAuthors">Dardenne et al.</title><title type="main">The alarmin <fc>HMGB</fc>‐1 influences healing outcomes in fetal skin wounds</title></titleGroup><creators><creator affiliationRef="#wrr12028-aff-0001" creatorRole="author" xml:id="wrr12028-cr-0001"><personName><givenNames>Adrienne D.</givenNames><familyName>Dardenne</familyName><degrees>DVM, MS</degrees></personName></creator><creator affiliationRef="#wrr12028-aff-0002" creatorRole="author" xml:id="wrr12028-cr-0002"><personName><givenNames>Brian C.</givenNames><familyName>Wulff</familyName><degrees>PhD</degrees></personName></creator><creator affiliationRef="#wrr12028-aff-0002" corresponding="yes" creatorRole="author" xml:id="wrr12028-cr-0003"><personName><givenNames>Traci A.</givenNames><familyName>Wilgus</familyName><degrees>PhD</degrees></personName></creator></creators><affiliationGroup><affiliation countryCode="US" xml:id="wrr12028-aff-0001"><orgDiv>Department of Veterinary Preventive Medicine</orgDiv><orgDiv>University Laboratory Animal Resources</orgDiv><orgName>The Ohio State University</orgName><address><city>Columbus</city><countryPart>Ohio</countryPart></address></affiliation><affiliation countryCode="US" xml:id="wrr12028-aff-0002"><orgDiv>Department of Pathology</orgDiv><orgName>The Ohio State University</orgName><address><city>Columbus</city><countryPart>Ohio</countryPart></address></affiliation></affiliationGroup><fundingInfo><fundingAgency>Ohio State University Department of Pathology</fundingAgency></fundingInfo><fundingInfo><fundingAgency>NIH</fundingAgency><fundingNumber>R01‐CA127109</fundingNumber></fundingInfo><supportingInformation><supportingInfoItem><mediaResource alt="pdf" href="urn-x:wiley:10671927:media:wrr12028:wrr12028-sup-0001-si"></mediaResource><caption><p><b>Figure S1.</b> Wound closure and cellular apoptosis are unaffected by HMGB‐1 in E15 fetal wounds. Wound closure was determined by examining histologic sections (A). Serial sections of the entire length of the wound were taken to ensure accuracy. All wounds, whether treated with PBS or HMGB‐1, were unhealed at 12 hours post‐wounding (not shown). Similar percentages of wounds contained an intact epithelial layer at 24 hours (25% or 2/8 wounds for PBS; 28% or 2/7 wounds for HMGB‐1). All wounds, regardless of treatment, were completely reepithelialized by 48 hours (<i>n</i> = 4–8 per group at each time point). Immunohistochemical staining for cleaved caspase‐3 was used to identify apoptotic cells (B–E). The number of cleaved caspase‐3‐positive cells was counted in the skin adjacent to the wound at 1 day (B) or in the wound bed at 3 and 7 days post‐wounding (C). Bars represent average number of positive cells per high‐power field (HPF) ± SEM (<i>n</i> = 3–5 per group at each time point). The data are presented as positive cells per HPF rather than positive cell density because of the low number of positive cells (0–2 cells per HPF). Similar results were obtained with TUNEL staining, except that the overall number of positive cells was slightly higher for all wounds (0–12 cells per HPF; data not shown). Representative sections stained for cleaved caspase‐3 are shown for E15 wounds injected with PBS (D) or 400 ng HMGB‐1 (E) at 7 days post‐wounding. Arrows are used to highlight positive cells; scale bar = 50 μm.</p></caption></supportingInfoItem><supportingInfoItem><mediaResource alt="tif" href="urn-x:wiley:10671927:media:wrr12028:wrr12028-sup-0002-si"></mediaResource><caption><p><b>Figure S2.</b> Mast cell density in fetal wounds treated with HMGB‐1.</p><p>Toluidine blue staining was used to evaluate mast cell density at the wound margin 12 and 24 hours postwounding (A). Bars represent average mast cell density (mast cell number per mm<sup>2</sup>) ± SEM (<i>n</i> = 3–5 per group). Representative toluidine blue‐stained sections of E15 wounds injected with PBS (B) or 400 ng HMGB‐1 (C) at 24 hours post‐wounding are shown.</p><p>Wound margins are marked with large arrows, and small arrows are used to highlight mast cells; scale bars = 100 μm.</p></caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main"><title type="main">Abstract</title><p>In mice, cutaneous wounds generated early in development (embryonic day 15, <fc>E</fc>15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, <fc>E</fc>18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (<fc>HMGB</fc>‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, <fc>E</fc>18 keratinocytes expressed higher levels of <fc>HMGB</fc>‐1 compared with <fc>E</fc>15 keratinocytes. After injury, <fc>HMGB</fc>‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming <fc>E</fc>18 wounds, compared with scarless <fc>E</fc>15 wounds. Furthermore, instead of healing scarlessly, <fc>E</fc>15 wounds healed with scars when treated with <fc>HMGB</fc>‐1. <fc>HMGB</fc>‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. Together, these data suggest that extracellular <fc>HMGB</fc>‐1 levels influence the quality of healing in cutaneous wounds.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>The alarmin HMGB‐1 influences healing outcomes in fetal skin wounds</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>HMGB‐1 and fetal wound healing</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>The alarmin HMGB‐1 influences healing outcomes in fetal skin wounds</title></titleInfo><name type="personal"><namePart type="given">Adrienne D.</namePart><namePart type="family">Dardenne</namePart><namePart type="termsOfAddress">DVM, MS</namePart><affiliation>Department of Veterinary Preventive Medicine, University Laboratory Animal Resources, The Ohio State University, Ohio, Columbus</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Brian C.</namePart><namePart type="family">Wulff</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Pathology, The Ohio State University, Ohio, Columbus</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Traci A.</namePart><namePart type="family">Wilgus</namePart><namePart type="termsOfAddress">PhD</namePart><affiliation>Department of Pathology, The Ohio State University, Ohio, Columbus</affiliation><affiliation>Dr. Traci A. Wilgus, PhD, Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA.Tel: 614 366‐8526;Fax: 614 366‐9389;Email:</affiliation><affiliation>E-mail: traci.wilgus@osumc.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2013-03</dateIssued><dateCreated encoding="w3cdtf">2013-01-14</dateCreated><dateCaptured encoding="w3cdtf">2012-07-12</dateCaptured><dateValid encoding="w3cdtf">2012-12-25</dateValid><copyrightDate encoding="w3cdtf">2013</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>In mice, cutaneous wounds generated early in development (embryonic day 15, E15) heal scarlessly, while wounds generated late in gestation (embryonic day 18, E18) heal with scar formation. Even though both types of wounds are generated in the same sterile uterine environment, scarless fetal wounds heal without inflammation, but a strong inflammatory response is observed in scar‐forming fetal wounds. We hypothesized that altered release of alarmins, endogenous molecules that trigger inflammation in response to damage, may be responsible for the age‐related changes in inflammation and healing outcomes in fetal skin. The purpose of this study was to determine whether the alarmin high‐mobility group box‐1 (HMGB‐1) is involved in fetal wound repair. Immunohistochemical analysis showed that in unwounded skin, E18 keratinocytes expressed higher levels of HMGB‐1 compared with E15 keratinocytes. After injury, HMGB‐1 was released to a greater extent from keratinocytes at the margin of scar‐forming E18 wounds, compared with scarless E15 wounds. Furthermore, instead of healing scarlessly, E15 wounds healed with scars when treated with HMGB‐1. HMGB‐1‐injected wounds also had more fibroblasts, blood vessels, and macrophages compared with control wounds. Together, these data suggest that extracellular HMGB‐1 levels influence the quality of healing in cutaneous wounds.</abstract><note type="additional physical form">Figure S1. Wound closure and cellular apoptosis are unaffected by HMGB‐1 in E15 fetal wounds. Wound closure was determined by examining histologic sections (A). Serial sections of the entire length of the wound were taken to ensure accuracy. All wounds, whether treated with PBS or HMGB‐1, were unhealed at 12 hours post‐wounding (not shown). Similar percentages of wounds contained an intact epithelial layer at 24 hours (25% or 2/8 wounds for PBS; 28% or 2/7 wounds for HMGB‐1). All wounds, regardless of treatment, were completely reepithelialized by 48 hours (n = 4–8 per group at each time point). Immunohistochemical staining for cleaved caspase‐3 was used to identify apoptotic cells (B–E). The number of cleaved caspase‐3‐positive cells was counted in the skin adjacent to the wound at 1 day (B) or in the wound bed at 3 and 7 days post‐wounding (C). Bars represent average number of positive cells per high‐power field (HPF) ± SEM (n = 3–5 per group at each time point). The data are presented as positive cells per HPF rather than positive cell density because of the low number of positive cells (0–2 cells per HPF). Similar results were obtained with TUNEL staining, except that the overall number of positive cells was slightly higher for all wounds (0–12 cells per HPF; data not shown). Representative sections stained for cleaved caspase‐3 are shown for E15 wounds injected with PBS (D) or 400 ng HMGB‐1 (E) at 7 days post‐wounding. Arrows are used to highlight positive cells; scale bar = 50 μm.Figure S2. Mast cell density in fetal wounds treated with HMGB‐1. Toluidine blue staining was used to evaluate mast cell density at the wound margin 12 and 24 hours postwounding (A). Bars represent average mast cell density (mast cell number per mm2) ± SEM (n = 3–5 per group). Representative toluidine blue‐stained sections of E15 wounds injected with PBS (B) or 400 ng HMGB‐1 (C) at 24 hours post‐wounding are shown. Wound margins are marked with large arrows, and small arrows are used to highlight mast cells; scale bars = 100 μm.</note><note type="funding">Ohio State University Department of Pathology</note><note type="funding">NIH - No. R01‐CA127109; </note><relatedItem type="host"><titleInfo><title>Wound Repair and Regeneration</title></titleInfo><titleInfo type="abbreviated"><title>Wound Repair Regen</title></titleInfo><genre type="journal">journal</genre><subject><genre>article-category</genre><topic>Original Research‐Basic Science</topic></subject><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>2013</date><detail type="volume"><caption>vol.</caption><number>21</number></detail><detail type="issue"><caption>no.</caption><number>2</number></detail><extent unit="pages"><start>282</start><end>291</end><total>10</total></extent></part></relatedItem><identifier type="istex">A96DCA10748A4825D1C6355B871575F1BF94F146</identifier><identifier type="DOI">10.1111/wrr.12028</identifier><identifier type="ArticleID">WRR12028</identifier><accessCondition type="use and reproduction" contentType="copyright">© 2013 Wound Healing Society© 2013 by the Wound Healing Society</accessCondition><recordInfo><recordContentSource>WILEY</recordContentSource></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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