Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice
| Autor: | Jenevieve D’souza, Pritishkumar Tidke, Sophiya Siddiqui, Indraneel Mittra, Kavita Pal, Vishal Jadhav, Bhagyeshri Rane, Saili Parab, Namrata Pancholi, Gorantla V. Raghuram, Sushma Shinde, Alfina Shaikh, Soniya Shende |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Hydrolases Physiology Apoptosis 030204 cardiovascular system & hematology Pathology and Laboratory Medicine Biochemistry Histones Mice 0302 clinical medicine Immune Physiology Medicine and Health Sciences Immune Response Innate Immune System Multidisciplinary Deoxyribonucleases biology Cell Death Chemistry Chromatin Enzymes Nucleic acids medicine.anatomical_structure Cell Processes Cytokines Medicine Female medicine.symptom Antibody Inflammation Mediators Cell-Free Nucleic Acids Research Article Programmed cell death DNA damage Nucleases Science Immunology Spleen Inflammation Microbiology Proinflammatory cytokine Sepsis 03 medical and health sciences Signs and Symptoms Diagnostic Medicine Virology DNA-binding proteins medicine Genetics Animals Deoxyribonuclease I Host Cells Biology and Life Sciences Proteins Cell Biology DNA Molecular Development medicine.disease Endotoxins Mice Inbred C57BL 030104 developmental biology Resveratrol Immune System biology.protein Enzymology Nanoparticles Viral Transmission and Infection Copper Developmental Biology |
| Zdroj: | PLoS ONE, Vol 15, Iss 3, p e0229017 (2020) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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