Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis
Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role i...
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| Veröffentlicht in: | PloS one 2016-02, Vol.11 (2), p.e0148142-e0148142 |
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| creator | Czaikoski, Paula Giselle Mota, José Maurício Segundo Correia Nascimento, Daniele Carvalho Sônego, Fabiane Castanheira, Fernanda Vargas e Silva Melo, Paulo Henrique Scortegagna, Gabriela Trentin Silva, Rangel Leal Barroso-Sousa, Romualdo Souto, Fabrício Oliveira Pazin-Filho, Antonio Figueiredo, Florencio Alves-Filho, José Carlos Cunha, Fernando Queiróz |
| description | Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis. |
| doi_str_mv | 10.1371/journal.pone.0148142 |
| format | Article |
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Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0148142</identifier><identifier>PMID: 26849138</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antibiotics ; Antimicrobial agents ; Apoptosis ; Bacteria ; Bacterial Load - drug effects ; Biochemistry ; Biodegradation ; Biology and Life Sciences ; Cecum ; Complications and side effects ; Cystic fibrosis ; Damage ; Degradation ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA - genetics ; DNA - metabolism ; Endotoxemia ; Enzymes ; Ertapenem ; Extracellular Traps - metabolism ; Free radicals ; Health aspects ; Humans ; Immunology ; Infections ; Kidneys ; Laboratory animals ; Lipopolysaccharides - pharmacology ; Medical schools ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Microorganisms ; Multiple organ failure ; Multiple Organ Failure - complications ; Neutrophils ; Pathogenesis ; Pathogens ; Patients ; Peripheral blood ; Pharmacology ; Physical Sciences ; Risk factors ; Rodents ; Sepsis ; Septic shock ; Shock ; Shock, Septic - chemically induced ; Shock, Septic - genetics ; Shock, Septic - microbiology ; Shock, Septic - pathology ; Surgery</subject><ispartof>PloS one, 2016-02, Vol.11 (2), p.e0148142-e0148142</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Czaikoski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Czaikoski et al 2016 Czaikoski et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-6dd714935047fda383ed0af982af3288b4f84e4efaeeeff4444410a9d79039833</citedby><cites>FETCH-LOGICAL-c692t-6dd714935047fda383ed0af982af3288b4f84e4efaeeeff4444410a9d79039833</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743982/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743982/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26849138$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Efron, Philip Alexander</contributor><creatorcontrib>Czaikoski, Paula Giselle</creatorcontrib><creatorcontrib>Mota, José Maurício Segundo Correia</creatorcontrib><creatorcontrib>Nascimento, Daniele Carvalho</creatorcontrib><creatorcontrib>Sônego, Fabiane</creatorcontrib><creatorcontrib>Castanheira, Fernanda Vargas e Silva</creatorcontrib><creatorcontrib>Melo, Paulo Henrique</creatorcontrib><creatorcontrib>Scortegagna, Gabriela Trentin</creatorcontrib><creatorcontrib>Silva, Rangel Leal</creatorcontrib><creatorcontrib>Barroso-Sousa, Romualdo</creatorcontrib><creatorcontrib>Souto, Fabrício Oliveira</creatorcontrib><creatorcontrib>Pazin-Filho, Antonio</creatorcontrib><creatorcontrib>Figueiredo, Florencio</creatorcontrib><creatorcontrib>Alves-Filho, José Carlos</creatorcontrib><creatorcontrib>Cunha, Fernando Queiróz</creatorcontrib><title>Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.</description><subject>Animals</subject><subject>Antibiotics</subject><subject>Antimicrobial agents</subject><subject>Apoptosis</subject><subject>Bacteria</subject><subject>Bacterial Load - drug effects</subject><subject>Biochemistry</subject><subject>Biodegradation</subject><subject>Biology and Life Sciences</subject><subject>Cecum</subject><subject>Complications and side effects</subject><subject>Cystic fibrosis</subject><subject>Damage</subject><subject>Degradation</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA - genetics</subject><subject>DNA - metabolism</subject><subject>Endotoxemia</subject><subject>Enzymes</subject><subject>Ertapenem</subject><subject>Extracellular Traps - metabolism</subject><subject>Free radicals</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Immunology</subject><subject>Infections</subject><subject>Kidneys</subject><subject>Laboratory animals</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Medical schools</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microorganisms</subject><subject>Multiple organ failure</subject><subject>Multiple Organ Failure - complications</subject><subject>Neutrophils</subject><subject>Pathogenesis</subject><subject>Pathogens</subject><subject>Patients</subject><subject>Peripheral blood</subject><subject>Pharmacology</subject><subject>Physical Sciences</subject><subject>Risk factors</subject><subject>Rodents</subject><subject>Sepsis</subject><subject>Septic shock</subject><subject>Shock</subject><subject>Shock, Septic - chemically induced</subject><subject>Shock, Septic - genetics</subject><subject>Shock, Septic - 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Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Czaikoski, Paula Giselle</au><au>Mota, José Maurício Segundo Correia</au><au>Nascimento, Daniele Carvalho</au><au>Sônego, Fabiane</au><au>Castanheira, Fernanda Vargas e Silva</au><au>Melo, Paulo Henrique</au><au>Scortegagna, Gabriela Trentin</au><au>Silva, Rangel Leal</au><au>Barroso-Sousa, Romualdo</au><au>Souto, Fabrício Oliveira</au><au>Pazin-Filho, Antonio</au><au>Figueiredo, Florencio</au><au>Alves-Filho, José Carlos</au><au>Cunha, Fernando Queiróz</au><au>Efron, Philip Alexander</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-02-05</date><risdate>2016</risdate><volume>11</volume><issue>2</issue><spage>e0148142</spage><epage>e0148142</epage><pages>e0148142-e0148142</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Organ dysfunction is a major concern in sepsis pathophysiology and contributes to its high mortality rate. Neutrophil extracellular traps (NETs) have been implicated in endothelial damage and take part in the pathogenesis of organ dysfunction in several conditions. NETs also have an important role in counteracting invading microorganisms during infection. The aim of this study was to evaluate systemic NETs formation, their participation in host bacterial clearance and their contribution to organ dysfunction in sepsis. C57Bl/6 mice were subjected to endotoxic shock or a polymicrobial sepsis model induced by cecal ligation and puncture (CLP). The involvement of cf-DNA/NETs in the physiopathology of sepsis was evaluated through NETs degradation by rhDNase. This treatment was also associated with a broad-spectrum antibiotic treatment (ertapenem) in mice after CLP. CLP or endotoxin administration induced a significant increase in the serum concentrations of NETs. The increase in CLP-induced NETs was sustained over a period of 3 to 24 h after surgery in mice and was not inhibited by the antibiotic treatment. Systemic rhDNase treatment reduced serum NETs and increased the bacterial load in non-antibiotic-treated septic mice. rhDNase plus antibiotics attenuated sepsis-induced organ damage and improved the survival rate. The correlation between the presence of NETs in peripheral blood and organ dysfunction was evaluated in 31 septic patients. Higher cf-DNA concentrations were detected in septic patients in comparison with healthy controls, and levels were correlated with sepsis severity and organ dysfunction. In conclusion, cf-DNA/NETs are formed during sepsis and are associated with sepsis severity. In the experimental setting, the degradation of NETs by rhDNase attenuates organ damage only when combined with antibiotics, confirming that NETs take part in sepsis pathogenesis. Altogether, our results suggest that NETs are important for host bacterial control and are relevant actors in the pathogenesis of sepsis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26849138</pmid><doi>10.1371/journal.pone.0148142</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-02, Vol.11 (2), p.e0148142-e0148142 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1762831601 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Antibiotics Antimicrobial agents Apoptosis Bacteria Bacterial Load - drug effects Biochemistry Biodegradation Biology and Life Sciences Cecum Complications and side effects Cystic fibrosis Damage Degradation Deoxyribonucleic acid Development and progression DNA DNA - genetics DNA - metabolism Endotoxemia Enzymes Ertapenem Extracellular Traps - metabolism Free radicals Health aspects Humans Immunology Infections Kidneys Laboratory animals Lipopolysaccharides - pharmacology Medical schools Medicine and Health Sciences Mice Mice, Inbred C57BL Microorganisms Multiple organ failure Multiple Organ Failure - complications Neutrophils Pathogenesis Pathogens Patients Peripheral blood Pharmacology Physical Sciences Risk factors Rodents Sepsis Septic shock Shock Shock, Septic - chemically induced Shock, Septic - genetics Shock, Septic - microbiology Shock, Septic - pathology Surgery |
| title | Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis |
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