Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice.
We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines....
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0229017 |
| _version_ | 1797823622487736320 |
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| author | Indraneel Mittra Kavita Pal Namrata Pancholi Pritishkumar Tidke Sophiya Siddiqui Bhagyeshri Rane Jenevieve D'souza Alfina Shaikh Saili Parab Sushma Shinde Vishal Jadhav Soniya Shende Gorantla V Raghuram |
| author_facet | Indraneel Mittra Kavita Pal Namrata Pancholi Pritishkumar Tidke Sophiya Siddiqui Bhagyeshri Rane Jenevieve D'souza Alfina Shaikh Saili Parab Sushma Shinde Vishal Jadhav Soniya Shende Gorantla V Raghuram |
| author_sort | Indraneel Mittra |
| collection | DOAJ |
| description | We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component. Female C57 BL/6 mice, 6-8 weeks old, were administered a single i.p. injection of LPS at a dose of 10 mg/Kg or 20 mg/Kg with or without concurrent treatment with the above cfCh inactivating agents. Administration of cfCh inactivating agents concurrently with LPS resulted in prevention of following pathological parameters: 1) release of cfCh in extra-cellular spaces of brain, lung and heart and in circulation; 2) release of inflammatory cytokines in circulation; 3) activation of DNA damage, apoptosis and inflammation in cells of thymus, spleen and in PBMCs; 4) DNA damage, apoptosis and inflammation in cells of lung, liver, heart, brain, kidney and small intestine; 5) liver and kidney dysfunction and elevation of serum lactate; 6) coagulopathy, fibrinolysis and thrombocytopenia; 7) lethality. We conclude that cfCh that are released from dying host cells in response to bacterial endotoxin represents a global instigator of sepsis. cfCh inactivation may provide a novel approach to management of sepsis in humans. |
| first_indexed | 2024-03-13T10:26:37Z |
| format | Article |
| id | doaj.art-37ecbbdffa834b81bfe244a5ba448a20 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-03-13T10:26:37Z |
| publishDate | 2020-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-37ecbbdffa834b81bfe244a5ba448a202023-05-19T05:31:15ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01153e022901710.1371/journal.pone.0229017Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice.Indraneel MittraKavita PalNamrata PancholiPritishkumar TidkeSophiya SiddiquiBhagyeshri RaneJenevieve D'souzaAlfina ShaikhSaili ParabSushma ShindeVishal JadhavSoniya ShendeGorantla V RaghuramWe have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component. Female C57 BL/6 mice, 6-8 weeks old, were administered a single i.p. injection of LPS at a dose of 10 mg/Kg or 20 mg/Kg with or without concurrent treatment with the above cfCh inactivating agents. Administration of cfCh inactivating agents concurrently with LPS resulted in prevention of following pathological parameters: 1) release of cfCh in extra-cellular spaces of brain, lung and heart and in circulation; 2) release of inflammatory cytokines in circulation; 3) activation of DNA damage, apoptosis and inflammation in cells of thymus, spleen and in PBMCs; 4) DNA damage, apoptosis and inflammation in cells of lung, liver, heart, brain, kidney and small intestine; 5) liver and kidney dysfunction and elevation of serum lactate; 6) coagulopathy, fibrinolysis and thrombocytopenia; 7) lethality. We conclude that cfCh that are released from dying host cells in response to bacterial endotoxin represents a global instigator of sepsis. cfCh inactivation may provide a novel approach to management of sepsis in humans.https://doi.org/10.1371/journal.pone.0229017 |
| spellingShingle | Indraneel Mittra Kavita Pal Namrata Pancholi Pritishkumar Tidke Sophiya Siddiqui Bhagyeshri Rane Jenevieve D'souza Alfina Shaikh Saili Parab Sushma Shinde Vishal Jadhav Soniya Shende Gorantla V Raghuram Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. PLoS ONE |
| title | Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. |
| title_full | Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. |
| title_fullStr | Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. |
| title_full_unstemmed | Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. |
| title_short | Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice. |
| title_sort | cell free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice |
| url | https://doi.org/10.1371/journal.pone.0229017 |
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