Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma
Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain. To chara...
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| Veröffentlicht in: | American journal of respiratory and critical care medicine 2019-05, Vol.199 (9), p.1076-1085 |
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| creator | Lachowicz-Scroggins, Marrah E Dunican, Eleanor M Charbit, Annabelle R Raymond, Wilfred Looney, Mark R Peters, Michael C Gordon, Erin D Woodruff, Prescott G Lefrançais, Emma Phillips, Brenda R Mauger, David T Comhair, Suzy A Erzurum, Serpil C Johansson, Mats W Jarjour, Nizar N Coverstone, Andrea M Castro, Mario Hastie, Annette T Bleecker, Eugene R Fajt, Merritt L Wenzel, Sally E Israel, Elliot Levy, Bruce D Fahy, John V |
| description | Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain.
To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation.
We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase.
We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all
values |
| doi_str_mv | 10.1164/rccm.201810-1869OC |
| format | Article |
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To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation.
We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase.
We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all
values <0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in soluble NET components, and increases in caspase 1 activity and IL-1β (all
values <0.001). In
studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase.
High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.</description><identifier>ISSN: 1073-449X</identifier><identifier>EISSN: 1535-4970</identifier><identifier>DOI: 10.1164/rccm.201810-1869OC</identifier><identifier>PMID: 30888839</identifier><language>eng</language><publisher>United States: American Thoracic Society</publisher><subject>Acute Disease ; Adult ; Asthma ; Asthma - immunology ; Asthma - metabolism ; Asthma - physiopathology ; Blotting, Western ; Case-Control Studies ; Dehydrogenases ; Deoxyribonucleic acid ; DNA ; DNA - metabolism ; Extracellular Traps - physiology ; Female ; Gene expression ; Glucosephosphate Dehydrogenase - metabolism ; Humans ; Inflammasomes - physiology ; Inflammation ; Interleukin-6 - metabolism ; Interleukin-8 - metabolism ; Kinases ; Longitudinal Studies ; Male ; Middle Aged ; Neutrophils ; Neutrophils - physiology ; Original ; R&D ; Research & development</subject><ispartof>American journal of respiratory and critical care medicine, 2019-05, Vol.199 (9), p.1076-1085</ispartof><rights>Copyright American Thoracic Society May 1, 2019</rights><rights>Copyright © 2019 by the American Thoracic Society 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-3173-5662 ; 0000-0003-4014-5100</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30888839$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lachowicz-Scroggins, Marrah E</creatorcontrib><creatorcontrib>Dunican, Eleanor M</creatorcontrib><creatorcontrib>Charbit, Annabelle R</creatorcontrib><creatorcontrib>Raymond, Wilfred</creatorcontrib><creatorcontrib>Looney, Mark R</creatorcontrib><creatorcontrib>Peters, Michael C</creatorcontrib><creatorcontrib>Gordon, Erin D</creatorcontrib><creatorcontrib>Woodruff, Prescott G</creatorcontrib><creatorcontrib>Lefrançais, Emma</creatorcontrib><creatorcontrib>Phillips, Brenda R</creatorcontrib><creatorcontrib>Mauger, David T</creatorcontrib><creatorcontrib>Comhair, Suzy A</creatorcontrib><creatorcontrib>Erzurum, Serpil C</creatorcontrib><creatorcontrib>Johansson, Mats W</creatorcontrib><creatorcontrib>Jarjour, Nizar N</creatorcontrib><creatorcontrib>Coverstone, Andrea M</creatorcontrib><creatorcontrib>Castro, Mario</creatorcontrib><creatorcontrib>Hastie, Annette T</creatorcontrib><creatorcontrib>Bleecker, Eugene R</creatorcontrib><creatorcontrib>Fajt, Merritt L</creatorcontrib><creatorcontrib>Wenzel, Sally E</creatorcontrib><creatorcontrib>Israel, Elliot</creatorcontrib><creatorcontrib>Levy, Bruce D</creatorcontrib><creatorcontrib>Fahy, John V</creatorcontrib><title>Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma</title><title>American journal of respiratory and critical care medicine</title><addtitle>Am J Respir Crit Care Med</addtitle><description>Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain.
To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation.
We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase.
We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all
values <0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in soluble NET components, and increases in caspase 1 activity and IL-1β (all
values <0.001). In
studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase.
High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.</description><subject>Acute Disease</subject><subject>Adult</subject><subject>Asthma</subject><subject>Asthma - immunology</subject><subject>Asthma - metabolism</subject><subject>Asthma - physiopathology</subject><subject>Blotting, Western</subject><subject>Case-Control Studies</subject><subject>Dehydrogenases</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA - metabolism</subject><subject>Extracellular Traps - physiology</subject><subject>Female</subject><subject>Gene expression</subject><subject>Glucosephosphate Dehydrogenase - metabolism</subject><subject>Humans</subject><subject>Inflammasomes - physiology</subject><subject>Inflammation</subject><subject>Interleukin-6 - metabolism</subject><subject>Interleukin-8 - metabolism</subject><subject>Kinases</subject><subject>Longitudinal Studies</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neutrophils</subject><subject>Neutrophils - physiology</subject><subject>Original</subject><subject>R&D</subject><subject>Research & development</subject><issn>1073-449X</issn><issn>1535-4970</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNpdUEtLAzEQDqLYuvoHPMiCFw_dmudmcxFKrVoo7cEK3kI2m9ot-zLZLfrvTbGKdS4zzDd8jwHgEsEhQjG9tVqXQwxRgmCEklgsxkegjxhhERUcHvsZchJRKl574My5DYQI-9tT0CMw8UVEH8jJR2uVNkXRFcqG9_PRIJybrrV1s86L8BBdWtW4QaiqLJxWq0KVpXJ1acKRbvOtavO6CvMqfDZbY_3StetSnYOTlSqcudj3ALw8TJbjp2i2eJyOR7OowYK2UUpjnBGDU05hljEj4kRwzlEaa4IzqvmKUk2ZIJirhDKYUJ4hiEXMMMFIaBKAu2_epktLk2lTeeOFbGxeKvspa5XLQ6TK1_Kt3sqYIZZw4glu9gS2fu-Ma2WZu11yVZm6c9KreH3IvWAArv-dburOVj6exBjvHFH_-ABc_XX0a-Xn9-QLKzKG6w</recordid><startdate>20190501</startdate><enddate>20190501</enddate><creator>Lachowicz-Scroggins, Marrah E</creator><creator>Dunican, Eleanor M</creator><creator>Charbit, Annabelle R</creator><creator>Raymond, Wilfred</creator><creator>Looney, Mark R</creator><creator>Peters, Michael C</creator><creator>Gordon, Erin D</creator><creator>Woodruff, Prescott G</creator><creator>Lefrançais, Emma</creator><creator>Phillips, Brenda R</creator><creator>Mauger, David T</creator><creator>Comhair, Suzy A</creator><creator>Erzurum, Serpil C</creator><creator>Johansson, Mats W</creator><creator>Jarjour, Nizar N</creator><creator>Coverstone, Andrea M</creator><creator>Castro, Mario</creator><creator>Hastie, Annette T</creator><creator>Bleecker, Eugene R</creator><creator>Fajt, Merritt L</creator><creator>Wenzel, Sally E</creator><creator>Israel, Elliot</creator><creator>Levy, Bruce D</creator><creator>Fahy, John V</creator><general>American Thoracic Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3173-5662</orcidid><orcidid>https://orcid.org/0000-0003-4014-5100</orcidid></search><sort><creationdate>20190501</creationdate><title>Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma</title><author>Lachowicz-Scroggins, Marrah E ; Dunican, Eleanor M ; Charbit, Annabelle R ; Raymond, Wilfred ; Looney, Mark R ; Peters, Michael C ; Gordon, Erin D ; Woodruff, Prescott G ; Lefrançais, Emma ; Phillips, Brenda R ; Mauger, David T ; Comhair, Suzy A ; Erzurum, Serpil C ; Johansson, Mats W ; Jarjour, Nizar N ; Coverstone, Andrea M ; Castro, Mario ; Hastie, Annette T ; Bleecker, Eugene R ; Fajt, Merritt L ; Wenzel, Sally E ; Israel, Elliot ; Levy, Bruce D ; Fahy, John V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p294t-b462d3e2b740dd5e96897771b6c32d4c7f44c459327a8450847d10296523219c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acute Disease</topic><topic>Adult</topic><topic>Asthma</topic><topic>Asthma - immunology</topic><topic>Asthma - metabolism</topic><topic>Asthma - physiopathology</topic><topic>Blotting, Western</topic><topic>Case-Control Studies</topic><topic>Dehydrogenases</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA - metabolism</topic><topic>Extracellular Traps - physiology</topic><topic>Female</topic><topic>Gene expression</topic><topic>Glucosephosphate Dehydrogenase - metabolism</topic><topic>Humans</topic><topic>Inflammasomes - physiology</topic><topic>Inflammation</topic><topic>Interleukin-6 - metabolism</topic><topic>Interleukin-8 - metabolism</topic><topic>Kinases</topic><topic>Longitudinal Studies</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neutrophils</topic><topic>Neutrophils - physiology</topic><topic>Original</topic><topic>R&D</topic><topic>Research & development</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lachowicz-Scroggins, Marrah E</creatorcontrib><creatorcontrib>Dunican, Eleanor M</creatorcontrib><creatorcontrib>Charbit, Annabelle R</creatorcontrib><creatorcontrib>Raymond, Wilfred</creatorcontrib><creatorcontrib>Looney, Mark R</creatorcontrib><creatorcontrib>Peters, Michael C</creatorcontrib><creatorcontrib>Gordon, Erin D</creatorcontrib><creatorcontrib>Woodruff, Prescott G</creatorcontrib><creatorcontrib>Lefrançais, Emma</creatorcontrib><creatorcontrib>Phillips, Brenda R</creatorcontrib><creatorcontrib>Mauger, David T</creatorcontrib><creatorcontrib>Comhair, Suzy A</creatorcontrib><creatorcontrib>Erzurum, Serpil C</creatorcontrib><creatorcontrib>Johansson, Mats W</creatorcontrib><creatorcontrib>Jarjour, Nizar N</creatorcontrib><creatorcontrib>Coverstone, Andrea M</creatorcontrib><creatorcontrib>Castro, Mario</creatorcontrib><creatorcontrib>Hastie, Annette T</creatorcontrib><creatorcontrib>Bleecker, Eugene R</creatorcontrib><creatorcontrib>Fajt, Merritt L</creatorcontrib><creatorcontrib>Wenzel, Sally E</creatorcontrib><creatorcontrib>Israel, Elliot</creatorcontrib><creatorcontrib>Levy, Bruce D</creatorcontrib><creatorcontrib>Fahy, John V</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of respiratory and critical care medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lachowicz-Scroggins, Marrah E</au><au>Dunican, Eleanor M</au><au>Charbit, Annabelle R</au><au>Raymond, Wilfred</au><au>Looney, Mark R</au><au>Peters, Michael C</au><au>Gordon, Erin D</au><au>Woodruff, Prescott G</au><au>Lefrançais, Emma</au><au>Phillips, Brenda R</au><au>Mauger, David T</au><au>Comhair, Suzy A</au><au>Erzurum, Serpil C</au><au>Johansson, Mats W</au><au>Jarjour, Nizar N</au><au>Coverstone, Andrea M</au><au>Castro, Mario</au><au>Hastie, Annette T</au><au>Bleecker, Eugene R</au><au>Fajt, Merritt L</au><au>Wenzel, Sally E</au><au>Israel, Elliot</au><au>Levy, Bruce D</au><au>Fahy, John V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma</atitle><jtitle>American journal of respiratory and critical care medicine</jtitle><addtitle>Am J Respir Crit Care Med</addtitle><date>2019-05-01</date><risdate>2019</risdate><volume>199</volume><issue>9</issue><spage>1076</spage><epage>1085</epage><pages>1076-1085</pages><issn>1073-449X</issn><eissn>1535-4970</eissn><abstract>Extracellular DNA (eDNA) and neutrophil extracellular traps (NETs) are implicated in multiple inflammatory diseases. NETs mediate inflammasome activation and IL-1β secretion from monocytes and cause airway epithelial cell injury, but the role of eDNA, NETs, and IL-1β in asthma is uncertain.
To characterize the role of activated neutrophils in severe asthma through measurement of NETs and inflammasome activation.
We measured sputum eDNA in induced sputum from 399 patients with asthma in the Severe Asthma Research Program-3 and in 94 healthy control subjects. We subdivided subjects with asthma into eDNA-low and -high subgroups to compare outcomes of asthma severity and of neutrophil and inflammasome activation. We also examined if NETs cause airway epithelial cell damage that can be prevented by DNase.
We found that 13% of the Severe Asthma Research Program-3 cohort is "eDNA-high," as defined by sputum eDNA concentrations above the upper 95th percentile value in health. Compared with eDNA-low patients with asthma, eDNA-high patients had lower Asthma Control Test scores, frequent history of chronic mucus hypersecretion, and frequent use of oral corticosteroids for maintenance of asthma control (all
values <0.05). Sputum eDNA in asthma was associated with airway neutrophilic inflammation, increases in soluble NET components, and increases in caspase 1 activity and IL-1β (all
values <0.001). In
studies, NETs caused cytotoxicity in airway epithelial cells that was prevented by disruption of NETs with DNase.
High extracellular DNA concentrations in sputum mark a subset of patients with more severe asthma who have NETs and markers of inflammasome activation in their airways.</abstract><cop>United States</cop><pub>American Thoracic Society</pub><pmid>30888839</pmid><doi>10.1164/rccm.201810-1869OC</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-3173-5662</orcidid><orcidid>https://orcid.org/0000-0003-4014-5100</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1073-449X |
| ispartof | American journal of respiratory and critical care medicine, 2019-05, Vol.199 (9), p.1076-1085 |
| issn | 1073-449X 1535-4970 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6515873 |
| source | MEDLINE; American Thoracic Society (ATS) Journals Online; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Acute Disease Adult Asthma Asthma - immunology Asthma - metabolism Asthma - physiopathology Blotting, Western Case-Control Studies Dehydrogenases Deoxyribonucleic acid DNA DNA - metabolism Extracellular Traps - physiology Female Gene expression Glucosephosphate Dehydrogenase - metabolism Humans Inflammasomes - physiology Inflammation Interleukin-6 - metabolism Interleukin-8 - metabolism Kinases Longitudinal Studies Male Middle Aged Neutrophils Neutrophils - physiology Original R&D Research & development |
| title | Extracellular DNA, Neutrophil Extracellular Traps, and Inflammasome Activation in Severe Asthma |
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