title: Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis.
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.
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Paula Giselle
authors: PG
authors: Czaikoski
authors: Department of Clinics, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: José Maurício Segundo Correia
authors: JM
authors: Mota
authors: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Daniele Carvalho
authors: DC
authors: Nascimento
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Fabiane
authors: F
authors: Sônego
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Fernanda Vargas e Silva
authors: FV
authors: Castanheira
authors: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Paulo Henrique
authors: PH
authors: Melo
authors: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Gabriela Trentin
authors: GT
authors: Scortegagna
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Rangel Leal
authors: RL
authors: Silva
authors: Department of Clinics, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Romualdo
authors: R
authors: Barroso-Sousa
authors: Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Fabrício Oliveira
authors: FO
authors: Souto
authors: Department of Clinics, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Antonio
authors: A
authors: Pazin-Filho
authors: Department of Pathology, School of Medicine, University of Brasilia, Brasilia, Brazil.
authors: Florencio
authors: F
authors: Figueiredo
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: José Carlos
authors: JC
authors: Alves-Filho
authors: Department of Pharmacology, Ribeirão Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
authors: Fernando Queiróz
authors: FQ
authors: Cunha
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000187:drug effects; D004247:DNA / Q000235:genetics / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009102:Multiple Organ Failure / Q000150:complications*; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000382:microbiology / Q000473:pathology*
chemical_list: D008070:Lipopolysaccharides; D004247:DNA