Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins
ABSTRACTAcute lung injury (ALI) and respiratory distress can develop as a consequence of sepsis with pathogens such as group A Streptococcus (GAS). In the pathogenesis of sepsis‐associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here,...
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| Veröffentlicht in: | The FASEB journal 2019-09, Vol.33 (9), p.10443-10452 |
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| creator | Rasmuson, Joel Kenne, Ellinor Wahlgren, Mats Soehnlein, Oliver Lindbom, Lennart |
| description | ABSTRACTAcute lung injury (ALI) and respiratory distress can develop as a consequence of sepsis with pathogens such as group A Streptococcus (GAS). In the pathogenesis of sepsis‐associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here, we find that sevuparin, a heparinoid with low anticoagulant activity, prevents neutrophil‐induced lung plasma leakage in a murine model of systemic inflammation evoked by heat‐killed GAS (hkGAS). Furthermore, using human neutrophils and endothelial cell monolayers, we demonstrate that sevuparin inhibits hkGAS‐induced endothelial barrier disruption by neutralizing the activity of neutrophil‐derived proteins. By mass spectrometry of neutrophil secretion, we identify proteins, including serprocidins, S100 proteins, and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Collectively, our results demonstrate the critical role of neutrophil‐derived proteins in vascular hyperpermeability caused by GAS and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.—Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O., Lindbom, L. Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins. FASEB J. 33, 10443–10452 (2019). www.fasebj.org |
| doi_str_mv | 10.1096/fj.201900627R |
| format | Article |
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In the pathogenesis of sepsis‐associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here, we find that sevuparin, a heparinoid with low anticoagulant activity, prevents neutrophil‐induced lung plasma leakage in a murine model of systemic inflammation evoked by heat‐killed GAS (hkGAS). Furthermore, using human neutrophils and endothelial cell monolayers, we demonstrate that sevuparin inhibits hkGAS‐induced endothelial barrier disruption by neutralizing the activity of neutrophil‐derived proteins. By mass spectrometry of neutrophil secretion, we identify proteins, including serprocidins, S100 proteins, and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Collectively, our results demonstrate the critical role of neutrophil‐derived proteins in vascular hyperpermeability caused by GAS and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.—Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O., Lindbom, L. Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins. 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In the pathogenesis of sepsis‐associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here, we find that sevuparin, a heparinoid with low anticoagulant activity, prevents neutrophil‐induced lung plasma leakage in a murine model of systemic inflammation evoked by heat‐killed GAS (hkGAS). Furthermore, using human neutrophils and endothelial cell monolayers, we demonstrate that sevuparin inhibits hkGAS‐induced endothelial barrier disruption by neutralizing the activity of neutrophil‐derived proteins. By mass spectrometry of neutrophil secretion, we identify proteins, including serprocidins, S100 proteins, and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Collectively, our results demonstrate the critical role of neutrophil‐derived proteins in vascular hyperpermeability caused by GAS and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.—Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O., Lindbom, L. Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins. FASEB J. 33, 10443–10452 (2019). www.fasebj.org</description><subject>Animals</subject><subject>Cell Adhesion</subject><subject>Endothelium, Vascular - immunology</subject><subject>Endothelium, Vascular - metabolism</subject><subject>Endothelium, Vascular - pathology</subject><subject>heparin</subject><subject>Heparin - analogs & derivatives</subject><subject>Heparin - pharmacology</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>inflammation</subject><subject>Lipopolysaccharides - toxicity</subject><subject>Male</subject><subject>Medicin och hälsovetenskap</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Neutrophils - immunology</subject><subject>Neutrophils - metabolism</subject><subject>Neutrophils - pathology</subject><subject>Pneumonia - etiology</subject><subject>Pneumonia - metabolism</subject><subject>Pneumonia - pathology</subject><subject>Pneumonia - prevention & control</subject><subject>S100 Proteins - metabolism</subject><subject>sepsis</subject><subject>Sepsis - complications</subject><subject>Sepsis - microbiology</subject><subject>Serine Proteases - metabolism</subject><subject>Streptococcal Infections - complications</subject><subject>Streptococcal Infections - microbiology</subject><subject>Streptococcus - pathogenicity</subject><subject>vascular permeability</subject><issn>0892-6638</issn><issn>1530-6860</issn><issn>1530-6860</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxi1ERZfCkSvKkUuKx87aiThB1aWgSpVaOFuOPel6m42DHW_VnvoIPCNPgmG3fy5wmhnr932e0UfIG6CHQBvxvlsdMgoNpYLJ82dkBnNOS1EL-pzMaN2wUghe75OXMa4opUBBvCD7HBiIisGMbE5w1MEN3tki4ib9HQo3LF3rplhcTAHHyRtvTIq_7n66wSaDttjoaFKvQ9GjviqmZfDpclkMmKage3frhsvt4Mel67POYnCbrBuDn9AN8RXZ63Qf8fWuHpDvi-NvRyfl6dnnL0cfT0tTcX5eMgm65ZqLViI0iGxuKKPCWuDAreEgBcyhbVjb5VNNLfOJnaUaeW1bLSU_IOXWN17jmFo1BrfW4UZ57dTu6Sp3qCpZNxIy3_yTz7vbR9G9ECoQos4RZO27rTaDPxLGSa1dNNj3ekCfomKsqoDTZv5kLRN8jAG7h4-Aqj-xqm6lHmPN_NuddWrXaB_o-xwz8GELXLseb_7vphYXn9ji6xP7381-tXQ</recordid><startdate>201909</startdate><enddate>201909</enddate><creator>Rasmuson, Joel</creator><creator>Kenne, Ellinor</creator><creator>Wahlgren, Mats</creator><creator>Soehnlein, Oliver</creator><creator>Lindbom, Lennart</creator><general>Federation of American Societies for Experimental Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>201909</creationdate><title>Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins</title><author>Rasmuson, Joel ; Kenne, Ellinor ; Wahlgren, Mats ; Soehnlein, Oliver ; Lindbom, Lennart</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c433R-271ab3a36b7e19ee25c0206dd1313dc3176151b92bf892c87000fd0ae38dba773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animals</topic><topic>Cell Adhesion</topic><topic>Endothelium, Vascular - immunology</topic><topic>Endothelium, Vascular - metabolism</topic><topic>Endothelium, Vascular - pathology</topic><topic>heparin</topic><topic>Heparin - analogs & derivatives</topic><topic>Heparin - pharmacology</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>inflammation</topic><topic>Lipopolysaccharides - toxicity</topic><topic>Male</topic><topic>Medicin och hälsovetenskap</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Neutrophils - immunology</topic><topic>Neutrophils - metabolism</topic><topic>Neutrophils - pathology</topic><topic>Pneumonia - etiology</topic><topic>Pneumonia - metabolism</topic><topic>Pneumonia - pathology</topic><topic>Pneumonia - prevention & control</topic><topic>S100 Proteins - metabolism</topic><topic>sepsis</topic><topic>Sepsis - complications</topic><topic>Sepsis - microbiology</topic><topic>Serine Proteases - metabolism</topic><topic>Streptococcal Infections - complications</topic><topic>Streptococcal Infections - microbiology</topic><topic>Streptococcus - pathogenicity</topic><topic>vascular permeability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rasmuson, Joel</creatorcontrib><creatorcontrib>Kenne, Ellinor</creatorcontrib><creatorcontrib>Wahlgren, Mats</creatorcontrib><creatorcontrib>Soehnlein, Oliver</creatorcontrib><creatorcontrib>Lindbom, Lennart</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><jtitle>The FASEB journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rasmuson, Joel</au><au>Kenne, Ellinor</au><au>Wahlgren, Mats</au><au>Soehnlein, Oliver</au><au>Lindbom, Lennart</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins</atitle><jtitle>The FASEB journal</jtitle><addtitle>FASEB J</addtitle><date>2019-09</date><risdate>2019</risdate><volume>33</volume><issue>9</issue><spage>10443</spage><epage>10452</epage><pages>10443-10452</pages><issn>0892-6638</issn><issn>1530-6860</issn><eissn>1530-6860</eissn><abstract>ABSTRACTAcute lung injury (ALI) and respiratory distress can develop as a consequence of sepsis with pathogens such as group A Streptococcus (GAS). In the pathogenesis of sepsis‐associated ALI, endothelial barrier disruption brought on by phagocyte activation is considered a causative factor. Here, we find that sevuparin, a heparinoid with low anticoagulant activity, prevents neutrophil‐induced lung plasma leakage in a murine model of systemic inflammation evoked by heat‐killed GAS (hkGAS). Furthermore, using human neutrophils and endothelial cell monolayers, we demonstrate that sevuparin inhibits hkGAS‐induced endothelial barrier disruption by neutralizing the activity of neutrophil‐derived proteins. By mass spectrometry of neutrophil secretion, we identify proteins, including serprocidins, S100 proteins, and histone H4, that interact with sevuparin and that are responsible for the disruptive effect on endothelial integrity. Collectively, our results demonstrate the critical role of neutrophil‐derived proteins in vascular hyperpermeability caused by GAS and suggest sevuparin as a potential therapeutic in acute neutrophilic inflammation.—Rasmuson, J., Kenne, E., Wahlgren, M., Soehnlein, O., Lindbom, L. Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins. FASEB J. 33, 10443–10452 (2019). www.fasebj.org</abstract><cop>United States</cop><pub>Federation of American Societies for Experimental Biology</pub><pmid>31216421</pmid><doi>10.1096/fj.201900627R</doi><tpages>10</tpages></addata></record> |
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| subjects | Animals Cell Adhesion Endothelium, Vascular - immunology Endothelium, Vascular - metabolism Endothelium, Vascular - pathology heparin Heparin - analogs & derivatives Heparin - pharmacology Histones - metabolism Humans inflammation Lipopolysaccharides - toxicity Male Medicin och hälsovetenskap Mice Mice, Inbred BALB C Neutrophils - immunology Neutrophils - metabolism Neutrophils - pathology Pneumonia - etiology Pneumonia - metabolism Pneumonia - pathology Pneumonia - prevention & control S100 Proteins - metabolism sepsis Sepsis - complications Sepsis - microbiology Serine Proteases - metabolism Streptococcal Infections - complications Streptococcal Infections - microbiology Streptococcus - pathogenicity vascular permeability |
| title | Heparinoid sevuparin inhibits Streptococcus‐induced vascular leak through neutralizing neutrophil‐derived proteins |
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