β-Lactams modulate neutrophil extracellular traps formation mediated by mTOR signaling pathway

Xie, Tian; Duan, Zhiwen; Sun, Shilong; Chu, Chengnan; Ding, Weiwei

doi:10.1016/j.bbrc.2020.11.067

Cited by 9 publications

(9 citation statements)

References 20 publications

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“…We followed the methods of Chu et al 2020 and Xie et al 2021 [ 20 , 27 ]. In brief, the cells were seeded at 5.2 × 10 4 cells per well in a 96-well plate in the culture media and were preincubated with antibiotics for 2 h at 37 °C in 5% CO2.…”

Section: Methodsmentioning

confidence: 99%

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De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

et al. 2021

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Empiric broad-spectrum antimicrobials therapy is suggested to be started immediately for sepsis patients. Empiric antimicrobial therapy should be narrowed once pathogen identification and sensitivities are established. However, the detailed mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular traps (NETs) played an essential role and de-escalation strategy might alleviate organs injury through regulation of NETs formation in sepsis. We evaluated the effect of imipenem and ceftriaxone on NETs formation in vitro and examined the role of reactive oxygen species (ROS). Next, we designed de-escalation and escalation strategy in cecum ligation and puncture (CLP) models. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. In CLP models, de-escalation therapy resulted in an increased serum MPO-DNA level during the early stage and decreased MPO-DNA level during late stage, which exerted the reverse effects in escalation therapy. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAse I during the early stage of sepsis (p < 0.01). Histopathological analysis showed decreased injury in lung, liver, and intestine in de-escalation therapy compared with escalation therapy (p < 0.01). De-escalation therapy results in the highest 6-day survival rate compared with the control group (p < 0.01), however, no significant difference was found between de-escalation and escalation group (p = 0.051). The in vitro study showed that the imipenem could promote, while the ceftriaxone could inhibit the formation of NETs in PMA-activated PMNs through a ROS-dependent manner. We firstly demonstrate that de-escalation, not escalation, therapy reduces organ injury, decreases inflammatory response by promoting NETs formation in the early stage, and inhibiting NETs formation in the late stage of sepsis.

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Section: Methodsmentioning

confidence: 99%

“…NETs visualization was performed according to previous protocols [ 27 ]. The neutrophils used for the plate reader assay were fixed with 4% PFA in PBS buffer for 30 min and permeabilized with 0.1% Triton X-100 for 30 min.…”

Section: Methodsmentioning

confidence: 99%

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

et al. 2021

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“…In addition to the production of oxidants including hypochlorous acid (HOCL), hydrogen peroxide (H 2 O 2 ) and superoxide (O 2 •− ), proteases, and chemokines, activated neutrophils are also capable of undergoing a process named netosis. The release of neutrophil extracellular traps (NETs) during netosis occurs when nuclear DNA decondenses to release web-like structures of linear DNA from the cell that are interlaced with histones, myeloperoxidase, and other antimicrobial peptides such as elastase [ 49 , 50 , 51 ]. NETs are able to trap and kill microorganisms owing to the activity of associated antimicrobial proteins, and they also limit parasite dissemination [ 52 ].…”

Section: Vascular Haemostasis In Sepsismentioning

confidence: 99%

“…For example, cold-inducible RNA-binding protein (CIRP), which is a DAMP, is known to be associated with organ injury and increased mortality in sepsis, and has recently been shown to enhance NETosis in the mice lungs during sepsis in an animal model induced by a cecal ligation and puncture (CLP) model [ 62 ]. Previous studies have also demonstrated that some antibiotics such as fluoroquinolones, macrolides, and a few b-lactams are capable of modulating the formation of NETs and, as such, may offer a protective role in early sepsis, this being ascribed to an immunomodulatory function possibly owing to downregulation of the PKC-Akt-mTOR pathway [ 50 ].…”

Section: Vascular Haemostasis In Sepsismentioning

confidence: 99%

Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention

2021

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Sepsis is regarded as one of the main causes of death among the critically ill. Pathogen infection results in a host-mediated pro-inflammatory response to fight infection; as part of this response, significant endogenous reactive oxygen (ROS) and nitrogen species (RNS) production occurs, instigated by a variety of sources, including activated inflammatory cells, such as neutrophils, platelets, and cells from the vascular endothelium. Inflammation can become an inappropriate self-sustaining and expansive process, resulting in sepsis. Patients with sepsis often exhibit loss of aspects of normal vascular homeostatic control, resulting in abnormal coagulation events and the development of disseminated intravascular coagulation. Diagnosis and treatment of sepsis remain a significant challenge for healthcare providers globally. Targeting the drivers of excessive oxidative/nitrosative stress using antioxidant treatments might be a therapeutic option. This review focuses on the association between excessive oxidative/nitrosative stress, a common feature in sepsis, and loss of homeostatic control at the level of the vasculature. The literature relating to potential antioxidants is also described.

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“…Cell-free DNA (cf-DNA) was reported as a marker for NET formation. We quantified the NET formation by detecting cf-DNA level as previously described (20). In general, SYTOX Green nucleic acid stain (ThermoFisher Scientific) was dissolved in RPMI 1640 at 5 μM.…”

Section: In Vitro Assay Of the Nfimentioning

confidence: 99%

Neutrophil extracellular trap formation index predicts occurrences of deep surgical site infection after laparotomy

Duan¹,

Sun²,

Qu³

et al. 2021

Ann Transl Med

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Background: Deep surgical site infections (DSSIs) are serious complications after laparotomy. Neutrophil extracellular traps (NETs) play a vital role in the development of DSSI. Here, we focused on a new approach to predicting the occurrence of DSSI through the detection of the NET formation index (NFI), and compared its prediction ability with other clinical infection indicators. Methods: Patients who received laparotomy were prospectively enrolled in this study. General information, APACHE II score, SOFA score, and serum infection indicators were recorded. The postoperative abdominal drainage fluid was collected within 3 days after the operation for quantification of the NFI.Results: A total of 92 consecutive patients were included, with 22 patients were diagnosed with DSSI.The NFI in the DSSI group was 32.70%±19.33% while the corresponding index was 10.70%±8.25% in the non-DSSI group (P<0.01). The mean APACHE II and SOFA score had significant differences between the two groups. The NFI was positively correlated with the APACHE II score (P<0.01, r=0.269) and SOFA score (P=0.013, r=0.258). Patients with a high NFI (NFI >13.86%) had a higher risk of developing DSSI.According to the receiver operating characteristic (ROC) curve, the area under the ROC curve (AUC) of the NFI, C-reactive protein (CRP) and procalcitonin (PCT) were 0.912, 0.748 and 0.731, respectively. Conclusions:In this cohort of surgical patients, the quantification of the NFI had a considerable predictive value for early identification of DSSI. The NFI in drainage fluid turned out to be a more sensitive and specific predictor of DSSI than serum infection indicators including CRP and PCT.

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β-Lactams modulate neutrophil extracellular traps formation mediated by mTOR signaling pathway

Cited by 9 publications

References 20 publications

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis

Clotting Dysfunction in Sepsis: A Role for ROS and Potential for Therapeutic Intervention

Neutrophil extracellular trap formation index predicts occurrences of deep surgical site infection after laparotomy

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