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Increased Circulating Levels of Neutrophil Extracellular Traps During Cardiopulmonary Bypass.

ABSTRACT: Background:The intensity of inflammatory response triggered by cardiopulmonary bypass (CPB) during cardiac surgery has been associated with adverse outcomes. Neutrophils might contribute to organ injury through the liberation of DNA histone-based structures named "neutrophil extracellular traps" (NETs). Our objective was to assess circulating NETs levels before and after cardiac surgery in low-risk and high-risk patients. Methods:This prospective cohort study included 2 groups of patients undergoing elective cardiac surgery with the use of CPB. The first group consisted of low-risk patients (European System for Cardiac Operative Risk Evaluation II ? 1%), and the second group included high-risk patients (European System for Cardiac Operative Risk Evaluation II ? 5%). Blood samples were drawn pre-CPB and 3 hours post-CPB separation. Measurements of circulating NETs, interleukin-6, C-reactive protein, myeloperoxidase, citrullinated histone 3, and pentraxin-related protein 3 levels were performed at each time point. Results:Twenty-four patients, 12 high-risk and 12 low-risk patients, were included. Circulating NETs measurements changed from a median of 0.054 before CPB to 0.084 at 3 hours post-CPB separation, with a median increase of 0.037 (P < 0.001) per patient. No difference was noted between the high-risk and low-risk groups. A linear relationship was found between the circulating NETs measurements 3 hours post-CPB and CPB duration (ß = 0.047; confidence interval, 0.012-0.081; P = 0.01 R2 = 0.27). A correlation was found between the change in NETs with citrullinated histone 3 and myeloperoxidase levels, but not between NETs and other inflammatory biomarkers. Conclusions:Circulating NETs measurements increases during cardiac surgery with postsurgical levels proportional to CPB duration. The clinical significance of NETs production during cardiac surgery should be further investigated.

SUBMITTER: Beaubien-Souligny W

PROVIDER: S-EPMC7067687 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Increased Circulating Levels of Neutrophil Extracellular Traps During Cardiopulmonary Bypass.

Beaubien-Souligny William W Neagoe Paul-Eduard PE Gagnon Daniel D Denault André Y AY Sirois Martin G MG

CJC open 20191216 2

<h4>Background</h4>The intensity of inflammatory response triggered by cardiopulmonary bypass (CPB) during cardiac surgery has been associated with adverse outcomes. Neutrophils might contribute to organ injury through the liberation of DNA histone-based structures named "neutrophil extracellular traps" (NETs). Our objective was to assess circulating NETs levels before and after cardiac surgery in low-risk and high-risk patients.<h4>Methods</h4>This prospective cohort study included 2 groups of ...[more]

PMID: 32190824

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Project description:BackgroundAs circulating DNA (cirDNA) is mainly detected as mononucleosome-associated circulating DNA (mono-N cirDNA) in blood, apoptosis has until now been considered as the main source of cirDNA. The mechanism of cirDNA release into the circulation, however, is still not fully understood. This work addresses that knowledge gap, working from the postulate that neutrophil extracellular traps (NET) may be a source of cirDNA, and by investigating whether NET may directly produce mono-N cirDNA.MethodsWe studied (1) the in vitro kinetics of cell derived genomic high molecular weight (gHMW) DNA degradation in serum; (2) the production of extracellular DNA and NET markers such as neutrophil elastase (NE) and myeloperoxidase (MPO) by ex vivo activated neutrophils; and (3) the in vitro NET degradation in serum; for this, we exploited the synergistic analytical information provided by specifically quantifying DNA by qPCR, and used shallow WGS and capillary electrophoresis to perform fragment size analysis. We also performed an in vivo study in knockout mice, and an in vitro study of gHMW DNA degradation, to elucidate the role of NE and MPO in effecting DNA degradation and fragmentation. We then compared the NET-associated markers and fragmentation size profiles of cirDNA in plasma obtained from patients with inflammatory diseases found to be associated with NET formation and high levels of cirDNA (COVID-19, N = 28; systemic lupus erythematosus, N = 10; metastatic colorectal cancer, N = 10; and from healthy individuals, N = 114).ResultsOur studies reveal that gHMW DNA degradation in serum results in the accumulation of mono-N DNA (81.3% of the remaining DNA following 24 h incubation in serum corresponded to mono-N DNA); "ex vivo" NET formation, as demonstrated by a concurrent 5-, 5-, and 35-fold increase of NE, MPO, and cell-free DNA (cfDNA) concentration in PMA-activated neutrophil culture supernatant, leads to the release of high molecular weight DNA that degrades down to mono-N in serum; NET mainly in the form of gHMW DNA generate mono-N cirDNA (2 and 41% of the remaining DNA after 2 h in serum corresponded to 1-10 kbp fragments and mono-N, respectively) independent of any cellular process when degraded in serum; NE and MPO may contribute synergistically to NET autocatabolism, resulting in a 25-fold decrease in total DNA concentration and a DNA fragment size profile similar to that observed from cirDNA following 8 h incubation with both NE and MPO; the cirDNA size profile of NE KO mice significantly differed from that of the WT, suggesting NE involvement in DNA degradation; and a significant increase in the levels of NE, MPO, and cirDNA was detected in plasma samples from lupus, COVID-19, and mCRC, showing a high correlation with these inflammatory diseases, while no correlation of NE and MPO with cirDNA was found in HI.ConclusionsOur work describes the mechanisms by which NET and cirDNA are linked. In doing so, we demonstrate that NET are a major source of mono-N cirDNA independent of apoptosis and establish a new paradigm of the mechanisms of cirDNA release in normal and pathological conditions. We also demonstrate a link between immune response and cirDNA.

Dataset Information

Increased Circulating Levels of Neutrophil Extracellular Traps During Cardiopulmonary Bypass.

Publications

Increased Circulating Levels of Neutrophil Extracellular Traps During Cardiopulmonary Bypass.

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