Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery

McIlroy, Daniel J.; Jarnicki, Andrew G.; Au, Gough G.; Lott, Natalie; Dw, Smith; Hansbro, Philip M.; Balogh, Zsolt J.

doi:10.1016/j.jcrc.2014.07.013

Cited by 140 publications

(150 citation statements)

References 25 publications

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“…in cystic fibrosis (53), lupus and associated nephritis (54), or acute respiratory distress syndrome (55)). Higher concentrations of chromatin in the circulation has been previously documented in burn and other critically ill patients (56–59), supporting the relevance of our model for human disease. Previous studies have suggested that the presence of MPO and elastase in tissues may be responsible for organ and tissue damages (60).…”

Section: Discussionsupporting

confidence: 85%

Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2

Inoue¹,

Kurihara

et al. 2016

Critical Care Medicine

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Background Innate immune dysfunction after major burn injuries increases the susceptibility to organ failure. Lipid mediators of inflammation resolution, e.g. Resolvin D2 (RvD2), have been shown recently to restore neutrophil functionality and reduce mortality rate in a rat model of major burn injury. However, the physiological mechanisms responsible for the benefic activity of RvD2 are not well understood. Design Prospective randomized animal investigation. Setting Academic research setting. Subjects Wistar male rats. Interventions Animals were subjected to a full thickness skin burn of 30% total body surface area. Two hours after burn, 25 ng/kg RvD2 was administered i.v. and repeated every day, for 8 days. At day 10 post burn (pb), 2 mg/kg of lipopolysaccharide (LPS) was administered i.v., and the presence of renal and hepatic injuries was evaluated at day 11 pb by immunohistochemistry and relevant blood chemistry. Measurements and Main Results In untreated animals, we found significant tissue damage in the kidney and liver, consistent with acute tubular necrosis and multifocal necrosis, and changes in blood chemistry, reflecting the deterioration of renal and hepatic functions. In RvD2 treated rats, we detected less tissue damage and significantly lower values of blood urea nitrogen (BUN) (26.4±2.1 vs. 36.0±9.3 mg/dl, p≤0.001), alanine aminotransferase (ALT) (266.5±295.2 vs. 861.8±813.7 U/l, p≤0.01), and total bilirubin (0.13±0.05 vs. 0.30±0.14 mg/dl, p≤0.01), compared to untreated animals. The mean blood pressure of all animals was above 65 mmHg, indicating adequate tissue perfusion throughout the experiments. We measured significantly larger amounts of chromatin in the circulation of untreated compared to RvD2 treated rats (575.1±331.0 vs. 264.1±122.4 ng/ml, p≤0.05) and identified neutrophil extracellular traps (NETs) in kidney and liver tissues from untreated rats, consistent with the tissue damage. Conclusions Pathological changes in kidney and liver tissues in a rat model of major burn and endotoxin insults are ameliorated by RvD2.

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Section: Discussionsupporting

confidence: 85%

Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2

Inoue¹,

Kurihara

et al. 2016

Critical Care Medicine

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“…Various studies have demonstrated that mtDNA is a critical activator of inflammation and the innate immune system (14,31). Some research reported that cellular injury released mtDNA into blood, which is a key link between trauma, inflammation, soluble immune response suppressor (SIRS) and acute lung injury in polytrauma patients and the elderly hip fracture model (12,13,16).…”

Section: Discussionmentioning

confidence: 99%

“…Previous results have suggested that early surgery increases mtDNA and cytokine release, which may subsequently aggravate the systemic inflammatory response and lung injury induced by elderly hip fracture (14)(15)(16). Hip fracture and surgery in elderly patients may induce systemic inflammatory responses and lung injury, which increases the risk of pulmonary infection and mortality during the post-injury period (12,13).…”

Section: Introductionmentioning

confidence: 99%

Early surgery increases mitochondrial DNA release and lung injury in a model of elderly hip fracture and chronic obstructive pulmonary disease

Zhang

Wang

et al. 2017

Exp Ther Med

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Abstract. Hip fractures are one of the most common injuries in elderly individuals and are associated with a high incidence of complications and mortality. Clinical guidelines recommend early reparative surgery within 24-48 h from hospital admission; however, it is currently unknown whether this principle of early surgery is applicable for patients with hip fracture and chronic obstructive pulmonary disease (COPD). To investigate the systemic inflammatory response and lung injury as a result early surgery in elderly patients with hip fracture and COPD, a COPD model was created, by daily exposure to cigarette smoke, and evaluated. Rats (5 months of age) were exposed to cigarette smoking for 37 weeks to create a COPD group.

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“…A identificação dos primeiros inibidores seletivos de PAD4 capazes de afetar a citrulinação celular confirma outros estudos que demonstraram que a inibição da atividade PAD4 é suficiente para interromper a produção das NETs em camundongos e em seres humanos (22)(23) . Produção e liberação de NETs em células intactas Estudos recentes mostram que as NETs mitocondriais são o principal tipo de NETs encontrados em lesões traumáticas e após cirurgias (24) . O tratamento de neutrófilos com fator estimulador de colônias de granulócitos (GM-CSF), seguido por ativação com fator do complemento C5a, resulta na liberação de NETs que contém DNA mitocondrial, por intermédio de um mecanismo independente de morte celular, mas que necessita da produção de EROs (8) .…”

Section: Resultsunclassified

Mecanismos Moleculares De Formação Das Armadilhas Extracelulares Dos Neutrófilos E Seu Papel Na Imunidade Inata

Andrade¹,

Penaforte²,

Veloso³

2016

ACS

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Conflito de interesses: Não Contribuição dos autores:FFDA concepção e planejamento do projeto de pesquisa, obtenção e interpretação dos dados, redação e revisão crítica. CLP interpretação dos dados, redação e revisão crítica. CAV concepção e planejamento do projeto de pesquisa, interpretação dos dados, redação e revisão crítica. Contato para correspondência: Clara Araújo Veloso E-mail: claraveloso@yahoo. Neutrophil extracellular traps are composed of chromatin, granular proteins, and some cytoplasmic proteins. Beyond elimination of various microorganisms, these structures also contribute to trap pathogens to the initial site of infection. Objective: Discuss the process of neutrophil extracellular traps formation, molecular mechanisms that regulate the production of these structures and their role in innate immunity. Material and Methods: Pubmed, Nature, Periódicos Capes, and PlosOne were searched from December 2014 to June 2015 using different combinations of the following descriptors: neutrophil extracellular traps, NETs, neutrophils, netosis, innate immunity, and bacteria. Studies associating molecular processes in the formation of neutrophil extracellular traps and/or about the antimicrobial activity of their components; experimental studies in vivo, in vitro and / or in silico were selected. Results: We found 1,383 articles and after using inclusion and exclusion criteria, 41 articles were selected. Different mechanisms are responsible in the formation of these traps. The dependence of the production of reactive oxygen species, the composition of these structures and involvement of cell death vary according to the stimulus. Conclusion: In spite of their beneficial effects during infections, evidence suggests that neutrophil extracellular traps have a negative impact in autoimmune and inflammatory diseases, thus, regulatory mechanism may be implicated in the decision of neutrophils to produce these structures. The identification of regulatory mechanisms of production of extracellular traps by neutrophils is crucial for the development of alternative therapies for diseases in which these structures are involved in the pathogenesis.

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Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery

Abstract: Neutrophil extracellular traps formed after major trauma and subsequent surgery contain mtDNA and represent a novel marker of heightened innate immune activation. They could be considered when timing surgery after trauma to prevent systemic NET-induced inflammatory complications.

Cited by 140 publications

References 25 publications

Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2

Kidney and Liver Injuries After Major Burns in Rats Are Prevented by Resolvin D2

Early surgery increases mitochondrial DNA release and lung injury in a model of elderly hip fracture and chronic obstructive pulmonary disease

Mecanismos Moleculares De Formação Das Armadilhas Extracelulares Dos Neutrófilos E Seu Papel Na Imunidade Inata

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