INVESTIGATION OF THE PATHOLOGICAL EFFECTS OF HISTONES, DNA, AND NUCLEOSOMES IN A MURINE MODEL OF SEPSIS.
Shock
; 60(2): 291-297, 2023 08 01.
Article
em En
| MEDLINE
| ID: mdl-37329563
ABSTRACT
ABSTRACT Background:
In sepsis, neutrophil extracellular traps (NETs) are an important interface between innate immunity and coagulation. The major structural component of neutrophil extracellular traps is nucleosomes (DNA-histone complexes). In vitro, DNA and histones exert procoagulant/cytotoxic effects whereas nucleosomes are not harmful. However, whether DNA, histones, and/or nucleosomes exert harmful effects in vivo remain unclear.Objectives:
(1) The aims of the study are to investigate the cytotoxic effects of nucleosomes ± DNase I and heparin in vitro and (2) to investigate whether DNA, histones, and/or nucleosomes are harmful when injected into healthy and septic mice.Methods:
The cytotoxic effects of DNA, histones, and nucleosomes (± DNaseI or ±heparin) were assessed in HEK293 cells. Mice underwent cecal ligation and puncture or sham surgery and then received injections of DNA (8 mg/kg), histones (8.5 mg/kg), or nucleosomes at 4 and 6 h. Organs and blood were harvested at 8 h. Cell-free DNA, IL-6, thrombin-anti-thrombin, and protein C were quantified from plasma.Results:
In vitro , incubation of HEK293 cells with DNaseI-treated nucleosomes reduced cell survival compared with nucleosome-treated cells, suggesting that DNaseI releases cytotoxic histones from nucleosomes. Addition of heparin to DNaseI-treated nucleosomes rescued cell death. In vivo, administration of histones to septic mice increased markers of inflammation (IL-6) and coagulation (thrombin-anti-thrombin), which was not observed in sham or septic mice administered DNA or nucleosomes.Conclusions:
Our studies suggest that DNA masks the harmful effects of histones in vitro and in vivo . Although administration of histones contributed to the pathogenesis of sepsis, administration of nucleosomes or DNA was not harmful in healthy or septic mice.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sepse
/
Armadilhas Extracelulares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Shock
Assunto da revista:
ANGIOLOGIA
/
CARDIOLOGIA
Ano de publicação:
2023
Tipo de documento:
Article