Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram‐negative sepsis (melioidosis)

Background: Melioidosis is a frequent cause of sepsis in Southeast Asia caused by the Gram‐negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of plasminogen activator inhibitor type 1 (PAI‐1), an important regulator of inflammation and fibrinolys...

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Veröffentlicht in:Journal of thrombosis and haemostasis 2011-10, Vol.9 (10), p.2020-2028
Hauptverfasser: KAGER, L. M., WIERSINGA, W. J., ROELOFS, J. J. T. H., MEIJERS, J. C. M., LEVI, M., Van'T VEER, C., van der POLL, T.
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container_end_page 2028
container_issue 10
container_start_page 2020
container_title Journal of thrombosis and haemostasis
container_volume 9
creator KAGER, L. M.
WIERSINGA, W. J.
ROELOFS, J. J. T. H.
MEIJERS, J. C. M.
LEVI, M.
Van'T VEER, C.
van der POLL, T.
description Background: Melioidosis is a frequent cause of sepsis in Southeast Asia caused by the Gram‐negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of plasminogen activator inhibitor type 1 (PAI‐1), an important regulator of inflammation and fibrinolysis. Objectives: In this study, we aimed to investigate the role of PAI‐1 during melioidosis. Methods: Wild‐type (WT) and PAI‐1‐deficient (PAI‐1–/1−/−) mice were intranasally infected with B. pseudomallei. Mice were killed after 24, 48 or 72 h. Lungs, liver and blood were harvested for measurement of bacterial loads, cytokines, clinical chemistry, histopathology, and coagulation parameters. Additionally, survival studies were performed. Results: PAI‐1−/− mice demonstrated enhanced susceptibility to B. pseudomallei infection, as shown by a strongly increased mortality rate (100% vs. 58% among WT mice, P 
doi_str_mv 10.1111/j.1538-7836.2011.04473.x
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M. ; WIERSINGA, W. J. ; ROELOFS, J. J. T. H. ; MEIJERS, J. C. M. ; LEVI, M. ; Van'T VEER, C. ; van der POLL, T.</creator><creatorcontrib>KAGER, L. M. ; WIERSINGA, W. J. ; ROELOFS, J. J. T. H. ; MEIJERS, J. C. M. ; LEVI, M. ; Van'T VEER, C. ; van der POLL, T.</creatorcontrib><description>Background: Melioidosis is a frequent cause of sepsis in Southeast Asia caused by the Gram‐negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of plasminogen activator inhibitor type 1 (PAI‐1), an important regulator of inflammation and fibrinolysis. Objectives: In this study, we aimed to investigate the role of PAI‐1 during melioidosis. Methods: Wild‐type (WT) and PAI‐1‐deficient (PAI‐1–/1−/−) mice were intranasally infected with B. pseudomallei. Mice were killed after 24, 48 or 72 h. Lungs, liver and blood were harvested for measurement of bacterial loads, cytokines, clinical chemistry, histopathology, and coagulation parameters. Additionally, survival studies were performed. Results: PAI‐1−/− mice demonstrated enhanced susceptibility to B. pseudomallei infection, as shown by a strongly increased mortality rate (100% vs. 58% among WT mice, P &lt; 0.001), associated with enhanced bacterial loads in lungs, liver, and blood. Additionally, PAI‐1−/− mice showed elevated levels of proinflammatory cytokines in lungs and plasma, accompanied by enhanced local and systemic coagulation activation (thrombin–antithrombin complexes and D‐dimer), increased hepatocellular injury (plasma aspartate aminotransferase and alanine aminotransferase), and renal failure (plasma creatinine and urea). Conclusions: PAI‐1 has a protective role during severe Gram‐negative sepsis caused by B. pseudomallei by limiting bacterial growth, inflammation, and coagulation, and probably, as a consequence thereof, distant organ injury.</description><identifier>ISSN: 1538-7933</identifier><identifier>ISSN: 1538-7836</identifier><identifier>EISSN: 1538-7836</identifier><identifier>DOI: 10.1111/j.1538-7836.2011.04473.x</identifier><identifier>PMID: 21848642</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Alanine transaminase ; Animals ; Aspartate aminotransferase ; Blood ; Burkholderia pseudomallei ; Burkholderia pseudomallei - growth &amp; development ; Burkholderia pseudomallei - isolation &amp; purification ; Coagulation ; Creatinine ; Cytokines ; Fibrinolysis ; Immunity ; Infection ; Inflammation ; Injuries ; Liver ; Lung ; Male ; Melioidosis ; Melioidosis - immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mortality ; Plasminogen Activator Inhibitor 1 - blood ; plasminogen activator inhibitor type 1 (PAI‐1) ; Plasminogen activator inhibitors ; Renal failure ; Sepsis ; Sepsis - immunology ; Sepsis - microbiology ; Survival ; Thrombosis ; Urea</subject><ispartof>Journal of thrombosis and haemostasis, 2011-10, Vol.9 (10), p.2020-2028</ispartof><rights>2011 International Society on Thrombosis and Haemostasis</rights><rights>2011 International Society on Thrombosis and Haemostasis.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4513-a19457bf84adaf93f1becfee743d1fd224a5a6fefe7c44a4c1fedfce0a1680a53</citedby><cites>FETCH-LOGICAL-c4513-a19457bf84adaf93f1becfee743d1fd224a5a6fefe7c44a4c1fedfce0a1680a53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21848642$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KAGER, L. M.</creatorcontrib><creatorcontrib>WIERSINGA, W. J.</creatorcontrib><creatorcontrib>ROELOFS, J. J. T. H.</creatorcontrib><creatorcontrib>MEIJERS, J. C. M.</creatorcontrib><creatorcontrib>LEVI, M.</creatorcontrib><creatorcontrib>Van'T VEER, C.</creatorcontrib><creatorcontrib>van der POLL, T.</creatorcontrib><title>Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram‐negative sepsis (melioidosis)</title><title>Journal of thrombosis and haemostasis</title><addtitle>J Thromb Haemost</addtitle><description>Background: Melioidosis is a frequent cause of sepsis in Southeast Asia caused by the Gram‐negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of plasminogen activator inhibitor type 1 (PAI‐1), an important regulator of inflammation and fibrinolysis. Objectives: In this study, we aimed to investigate the role of PAI‐1 during melioidosis. Methods: Wild‐type (WT) and PAI‐1‐deficient (PAI‐1–/1−/−) mice were intranasally infected with B. pseudomallei. Mice were killed after 24, 48 or 72 h. Lungs, liver and blood were harvested for measurement of bacterial loads, cytokines, clinical chemistry, histopathology, and coagulation parameters. Additionally, survival studies were performed. Results: PAI‐1−/− mice demonstrated enhanced susceptibility to B. pseudomallei infection, as shown by a strongly increased mortality rate (100% vs. 58% among WT mice, P &lt; 0.001), associated with enhanced bacterial loads in lungs, liver, and blood. Additionally, PAI‐1−/− mice showed elevated levels of proinflammatory cytokines in lungs and plasma, accompanied by enhanced local and systemic coagulation activation (thrombin–antithrombin complexes and D‐dimer), increased hepatocellular injury (plasma aspartate aminotransferase and alanine aminotransferase), and renal failure (plasma creatinine and urea). Conclusions: PAI‐1 has a protective role during severe Gram‐negative sepsis caused by B. pseudomallei by limiting bacterial growth, inflammation, and coagulation, and probably, as a consequence thereof, distant organ injury.</description><subject>Alanine transaminase</subject><subject>Animals</subject><subject>Aspartate aminotransferase</subject><subject>Blood</subject><subject>Burkholderia pseudomallei</subject><subject>Burkholderia pseudomallei - growth &amp; development</subject><subject>Burkholderia pseudomallei - isolation &amp; purification</subject><subject>Coagulation</subject><subject>Creatinine</subject><subject>Cytokines</subject><subject>Fibrinolysis</subject><subject>Immunity</subject><subject>Infection</subject><subject>Inflammation</subject><subject>Injuries</subject><subject>Liver</subject><subject>Lung</subject><subject>Male</subject><subject>Melioidosis</subject><subject>Melioidosis - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mortality</subject><subject>Plasminogen Activator Inhibitor 1 - blood</subject><subject>plasminogen activator inhibitor type 1 (PAI‐1)</subject><subject>Plasminogen activator inhibitors</subject><subject>Renal failure</subject><subject>Sepsis</subject><subject>Sepsis - immunology</subject><subject>Sepsis - microbiology</subject><subject>Survival</subject><subject>Thrombosis</subject><subject>Urea</subject><issn>1538-7933</issn><issn>1538-7836</issn><issn>1538-7836</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkU1u1DAUgC0EomXgCsg7ymKCHTsTZ8ECVfRPlcqirC3HeR48SuxgOzCzq8QFOAJn4SicpE6n7bLCXvhZ_t57tj-EMCUFzePDpqAVE8tasFVREkoLwnnNiu0zdPh48Pwhbhg7QK9i3BBCm6okL9FBSQUXK14eol9fehUH6_waHFY62R8q-YCt-2ZbO0dpN8LfP-dYe5eCbacEESePx-ATzDhgOwyTs2mHuylYt8awHSHYAVxSPT4Navh389vBWt3BEcZoIz4aoLfedj5v3r9GL4zqI7y5Xxfo68nn6-Oz5eXV6fnxp8ul5hVlS0UbXtWtEVx1yjTM0Ba0Aag566jpypKrSq0MGKg154praqAzGoiiK0FUxRbo3b5uvvz3CWKSg40a-l458FOUoqlEnvknF-joSZKSkgjWMEIzKvaoDj7GAEaO-fEq7DIkZ1lyI2cPcnYiZ1nyTpbc5tS3912mdoDuMfHBTgY-7oGftofdfxeWF9dnc8RuAVPBqao</recordid><startdate>201110</startdate><enddate>201110</enddate><creator>KAGER, L. M.</creator><creator>WIERSINGA, W. J.</creator><creator>ROELOFS, J. J. T. H.</creator><creator>MEIJERS, J. C. M.</creator><creator>LEVI, M.</creator><creator>Van'T VEER, C.</creator><creator>van der POLL, T.</creator><general>Blackwell Publishing Ltd</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>7QL</scope><scope>C1K</scope><scope>7X8</scope></search><sort><creationdate>201110</creationdate><title>Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram‐negative sepsis (melioidosis)</title><author>KAGER, L. M. ; WIERSINGA, W. J. ; ROELOFS, J. J. T. H. ; MEIJERS, J. C. M. ; LEVI, M. ; Van'T VEER, C. ; van der POLL, T.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4513-a19457bf84adaf93f1becfee743d1fd224a5a6fefe7c44a4c1fedfce0a1680a53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Alanine transaminase</topic><topic>Animals</topic><topic>Aspartate aminotransferase</topic><topic>Blood</topic><topic>Burkholderia pseudomallei</topic><topic>Burkholderia pseudomallei - growth &amp; development</topic><topic>Burkholderia pseudomallei - isolation &amp; purification</topic><topic>Coagulation</topic><topic>Creatinine</topic><topic>Cytokines</topic><topic>Fibrinolysis</topic><topic>Immunity</topic><topic>Infection</topic><topic>Inflammation</topic><topic>Injuries</topic><topic>Liver</topic><topic>Lung</topic><topic>Male</topic><topic>Melioidosis</topic><topic>Melioidosis - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mortality</topic><topic>Plasminogen Activator Inhibitor 1 - blood</topic><topic>plasminogen activator inhibitor type 1 (PAI‐1)</topic><topic>Plasminogen activator inhibitors</topic><topic>Renal failure</topic><topic>Sepsis</topic><topic>Sepsis - immunology</topic><topic>Sepsis - microbiology</topic><topic>Survival</topic><topic>Thrombosis</topic><topic>Urea</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>KAGER, L. M.</creatorcontrib><creatorcontrib>WIERSINGA, W. J.</creatorcontrib><creatorcontrib>ROELOFS, J. J. T. H.</creatorcontrib><creatorcontrib>MEIJERS, J. C. M.</creatorcontrib><creatorcontrib>LEVI, M.</creatorcontrib><creatorcontrib>Van'T VEER, C.</creatorcontrib><creatorcontrib>van der POLL, T.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of thrombosis and haemostasis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KAGER, L. M.</au><au>WIERSINGA, W. J.</au><au>ROELOFS, J. J. T. H.</au><au>MEIJERS, J. C. M.</au><au>LEVI, M.</au><au>Van'T VEER, C.</au><au>van der POLL, T.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram‐negative sepsis (melioidosis)</atitle><jtitle>Journal of thrombosis and haemostasis</jtitle><addtitle>J Thromb Haemost</addtitle><date>2011-10</date><risdate>2011</risdate><volume>9</volume><issue>10</issue><spage>2020</spage><epage>2028</epage><pages>2020-2028</pages><issn>1538-7933</issn><issn>1538-7836</issn><eissn>1538-7836</eissn><abstract>Background: Melioidosis is a frequent cause of sepsis in Southeast Asia caused by the Gram‐negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of plasminogen activator inhibitor type 1 (PAI‐1), an important regulator of inflammation and fibrinolysis. Objectives: In this study, we aimed to investigate the role of PAI‐1 during melioidosis. Methods: Wild‐type (WT) and PAI‐1‐deficient (PAI‐1–/1−/−) mice were intranasally infected with B. pseudomallei. Mice were killed after 24, 48 or 72 h. Lungs, liver and blood were harvested for measurement of bacterial loads, cytokines, clinical chemistry, histopathology, and coagulation parameters. Additionally, survival studies were performed. Results: PAI‐1−/− mice demonstrated enhanced susceptibility to B. pseudomallei infection, as shown by a strongly increased mortality rate (100% vs. 58% among WT mice, P &lt; 0.001), associated with enhanced bacterial loads in lungs, liver, and blood. Additionally, PAI‐1−/− mice showed elevated levels of proinflammatory cytokines in lungs and plasma, accompanied by enhanced local and systemic coagulation activation (thrombin–antithrombin complexes and D‐dimer), increased hepatocellular injury (plasma aspartate aminotransferase and alanine aminotransferase), and renal failure (plasma creatinine and urea). Conclusions: PAI‐1 has a protective role during severe Gram‐negative sepsis caused by B. pseudomallei by limiting bacterial growth, inflammation, and coagulation, and probably, as a consequence thereof, distant organ injury.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>21848642</pmid><doi>10.1111/j.1538-7836.2011.04473.x</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record>
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subjects Alanine transaminase
Animals
Aspartate aminotransferase
Blood
Burkholderia pseudomallei
Burkholderia pseudomallei - growth & development
Burkholderia pseudomallei - isolation & purification
Coagulation
Creatinine
Cytokines
Fibrinolysis
Immunity
Infection
Inflammation
Injuries
Liver
Lung
Male
Melioidosis
Melioidosis - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Mortality
Plasminogen Activator Inhibitor 1 - blood
plasminogen activator inhibitor type 1 (PAI‐1)
Plasminogen activator inhibitors
Renal failure
Sepsis
Sepsis - immunology
Sepsis - microbiology
Survival
Thrombosis
Urea
title Plasminogen activator inhibitor type I contributes to protective immunity during experimental Gram‐negative sepsis (melioidosis)
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