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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedema</title><author><name sortKey="Gardenier, Jason C" sort="Gardenier, Jason C" uniqKey="Gardenier J" first="Jason C." last="Gardenier">Jason C. Gardenier</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Hespe, Geoffrey E" sort="Hespe, Geoffrey E" uniqKey="Hespe G" first="Geoffrey E." last="Hespe">Geoffrey E. Hespe</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Kataru, Raghu P" sort="Kataru, Raghu P" uniqKey="Kataru R" first="Raghu P." last="Kataru">Raghu P. Kataru</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Savetsky, Ira L" sort="Savetsky, Ira L" uniqKey="Savetsky I" first="Ira L." last="Savetsky">Ira L. Savetsky</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Torrisi, Jeremy S" sort="Torrisi, Jeremy S" uniqKey="Torrisi J" first="Jeremy S." last="Torrisi">Jeremy S. Torrisi</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Nores, Gabriela D Garcia" sort="Nores, Gabriela D Garcia" uniqKey="Nores G" first="Gabriela D. García" last="Nores">Gabriela D. García Nores</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Dayan, Joseph J" sort="Dayan, Joseph J" uniqKey="Dayan J" first="Joseph J." last="Dayan">Joseph J. Dayan</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Chang, David" sort="Chang, David" uniqKey="Chang D" first="David" last="Chang">David Chang</name><affiliation><nlm:aff id="A2">Section of Plastic and Reconstructive Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.</nlm:aff></affiliation></author><author><name sortKey="Zampell, Jamie" sort="Zampell, Jamie" uniqKey="Zampell J" first="Jamie" last="Zampell">Jamie Zampell</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Martinez Corral, Ines" sort="Martinez Corral, Ines" uniqKey="Martinez Corral I" first="Inés" last="Martínez-Corral">Inés Martínez-Corral</name><affiliation><nlm:aff id="A3">Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Ortega, Sagrario" sort="Ortega, Sagrario" uniqKey="Ortega S" first="Sagrario" last="Ortega">Sagrario Ortega</name><affiliation><nlm:aff id="A4">Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.</nlm:aff></affiliation></author><author><name sortKey="Mehrara, Babak J" sort="Mehrara, Babak J" uniqKey="Mehrara B" first="Babak J." last="Mehrara">Babak J. Mehrara</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27699240</idno><idno type="pmc">5033805</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033805</idno><idno type="RBID">PMC:5033805</idno><idno type="doi">10.1172/jci.insight.84095</idno><date when="????">????</date><idno type="wicri:Area/Pmc/Corpus">003008</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">003008</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedema</title><author><name sortKey="Gardenier, Jason C" sort="Gardenier, Jason C" uniqKey="Gardenier J" first="Jason C." last="Gardenier">Jason C. Gardenier</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Hespe, Geoffrey E" sort="Hespe, Geoffrey E" uniqKey="Hespe G" first="Geoffrey E." last="Hespe">Geoffrey E. Hespe</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Kataru, Raghu P" sort="Kataru, Raghu P" uniqKey="Kataru R" first="Raghu P." last="Kataru">Raghu P. Kataru</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Savetsky, Ira L" sort="Savetsky, Ira L" uniqKey="Savetsky I" first="Ira L." last="Savetsky">Ira L. Savetsky</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Torrisi, Jeremy S" sort="Torrisi, Jeremy S" uniqKey="Torrisi J" first="Jeremy S." last="Torrisi">Jeremy S. Torrisi</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Nores, Gabriela D Garcia" sort="Nores, Gabriela D Garcia" uniqKey="Nores G" first="Gabriela D. García" last="Nores">Gabriela D. García Nores</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Dayan, Joseph J" sort="Dayan, Joseph J" uniqKey="Dayan J" first="Joseph J." last="Dayan">Joseph J. Dayan</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Chang, David" sort="Chang, David" uniqKey="Chang D" first="David" last="Chang">David Chang</name><affiliation><nlm:aff id="A2">Section of Plastic and Reconstructive Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.</nlm:aff></affiliation></author><author><name sortKey="Zampell, Jamie" sort="Zampell, Jamie" uniqKey="Zampell J" first="Jamie" last="Zampell">Jamie Zampell</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author><author><name sortKey="Martinez Corral, Ines" sort="Martinez Corral, Ines" uniqKey="Martinez Corral I" first="Inés" last="Martínez-Corral">Inés Martínez-Corral</name><affiliation><nlm:aff id="A3">Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.</nlm:aff></affiliation></author><author><name sortKey="Ortega, Sagrario" sort="Ortega, Sagrario" uniqKey="Ortega S" first="Sagrario" last="Ortega">Sagrario Ortega</name><affiliation><nlm:aff id="A4">Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.</nlm:aff></affiliation></author><author><name sortKey="Mehrara, Babak J" sort="Mehrara, Babak J" uniqKey="Mehrara B" first="Babak J." last="Mehrara">Babak J. Mehrara</name><affiliation><nlm:aff id="A1">Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</nlm:aff></affiliation></author></analytic><series><title level="j">JCI Insight</title><idno type="eISSN">2379-3708</idno><imprint><date when="????">????</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Development of novel treatments for lymphedema has been limited by the fact that the pathophysiology of this disease is poorly understood. It remains unknown, for example, why limb swelling resulting from surgical injury resolves initially, but recurs in some cases months or years later. Finding answers for these basic questions has been hampered by the lack of adequate animal models. In the current study, we used <italic>Cre-lox</italic> mice that expressed the human diphtheria toxin receptor (DTR) driven by a lymphatic-specific promoter in order to noninvasively ablate the lymphatic system of the hind limb. Animals treated in this manner developed lymphedema that was indistinguishable from clinical lymphedema temporally, radiographically, and histologically. Using this model and clinical biopsy specimens, we show that the initial resolution of edema after injury is dependent on the formation of collateral capillary lymphatics and that this process is regulated by M2-polarized macrophages. In addition, we show that despite these initial improvements in lymphatic function, persistent accumulation of CD4<sup>+</sup> cells inhibits lymphangiogenesis and promotes sclerosis of collecting lymphatics, resulting in late onset of edema and fibrosis. Our findings therefore provide strong evidence that inflammatory changes after lymphatic injury play a key role in the pathophysiology of lymphedema.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">JCI Insight</journal-id><journal-id journal-id-type="iso-abbrev">JCI Insight</journal-id><journal-id journal-id-type="publisher-id">JCI Insight</journal-id><journal-title-group><journal-title>JCI Insight</journal-title></journal-title-group><issn pub-type="epub">2379-3708</issn><publisher><publisher-name>American Society for Clinical Investigation</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27699240</article-id><article-id pub-id-type="pmc">5033805</article-id><article-id pub-id-type="publisher-id">84095</article-id><article-id pub-id-type="doi">10.1172/jci.insight.84095</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Diphtheria toxin–mediated ablation of lymphatic endothelial cells results in progressive lymphedema</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gardenier</surname><given-names>Jason C.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Hespe</surname><given-names>Geoffrey E.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Kataru</surname><given-names>Raghu P.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Savetsky</surname><given-names>Ira L.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Torrisi</surname><given-names>Jeremy S.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Nores</surname><given-names>Gabriela D. García</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Dayan</surname><given-names>Joseph J.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chang</surname><given-names>David</given-names></name><email>dchang@surgery.bsd.uchicago.edu</email><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Zampell</surname><given-names>Jamie</given-names></name><email>zampellj@gmail.com</email><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Martínez-Corral</surname><given-names>Inés</given-names></name><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Ortega</surname><given-names>Sagrario</given-names></name><email>Sortega@cnio.es</email><xref ref-type="aff" rid="A4">4</xref></contrib><contrib contrib-type="author"><name><surname>Mehrara</surname><given-names>Babak J.</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Surgery, Division of Plastic and Reconstructive Surgery, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA.</aff><aff id="A2"><label>2</label>Section of Plastic and Reconstructive Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois, USA.</aff><aff id="A3"><label>3</label>Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.</aff><aff id="A4"><label>4</label>Transgenic Mice Unit, Biotechnology Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.</aff><author-notes><corresp>Address correspondence to: Babak J. Mehrara, Memorial Hospital, Professor of Surgery (Plastic), Weill Cornell University Medical Center, 1275 York Avenue, Suite MRI 1006, New York, New York 10065, USA. Phone: 212.639.8639; E-mail address: <email>mehrarab@mskcc.org</email>.</corresp></author-notes><pub-date date-type="pub" publication-format="electronic" iso-8601-date="2016-09-22"><day>22</day><month>9</month><year>2016</year></pub-date><pub-date date-type="collection" publication-format="electronic" iso-8601-date="2016-09-22"><day>22</day><month>9</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>22</day><month>9</month><year>2016</year></pub-date><pmc-comment> PMC Release delay is 0 months and
0 days and was based on the
<volume>1</volume><issue>15</issue><elocation-id>e84095</elocation-id><history><date date-type="received"><day>4</day><month>8</month><year>2015</year></date><date date-type="accepted"><day>12</day><month>8</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, American Society for Clinical Investigation</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>American Society for Clinical Investigation</copyright-holder></permissions><self-uri xlink:href="https://insight.jci.org/articles/view/84095">This article is available online at https://insight.jci.org/articles/view/84095</self-uri><abstract><p>Development of novel treatments for lymphedema has been limited by the fact that the pathophysiology of this disease is poorly understood. It remains unknown, for example, why limb swelling resulting from surgical injury resolves initially, but recurs in some cases months or years later. Finding answers for these basic questions has been hampered by the lack of adequate animal models. In the current study, we used <italic>Cre-lox</italic> mice that expressed the human diphtheria toxin receptor (DTR) driven by a lymphatic-specific promoter in order to noninvasively ablate the lymphatic system of the hind limb. Animals treated in this manner developed lymphedema that was indistinguishable from clinical lymphedema temporally, radiographically, and histologically. Using this model and clinical biopsy specimens, we show that the initial resolution of edema after injury is dependent on the formation of collateral capillary lymphatics and that this process is regulated by M2-polarized macrophages. In addition, we show that despite these initial improvements in lymphatic function, persistent accumulation of CD4<sup>+</sup> cells inhibits lymphangiogenesis and promotes sclerosis of collecting lymphatics, resulting in late onset of edema and fibrosis. Our findings therefore provide strong evidence that inflammatory changes after lymphatic injury play a key role in the pathophysiology of lymphedema.</p></abstract><abstract abstract-type="toc"><p>A transgenic mouse model recapitulates progressive lymphedema and provides insights into the cellular mechanisms governing recovery and progression.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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