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

Abstract 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 unc...

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Autores principales: Zehua Duan, Tian Xie, Chengnan Chu, Fang Chen, Xinyu Wang, Jieshou Li, Weiwei Ding
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Publicado: Nature Publishing Group 2021
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spelling oai:doaj.org-article:591756b817a645679e99147ab43f9efa2021-11-14T12:12:26ZDe-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis10.1038/s41420-021-00745-02058-7716https://doaj.org/article/591756b817a645679e99147ab43f9efa2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00745-0https://doaj.org/toc/2058-7716Abstract 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.Zehua DuanTian XieChengnan ChuFang ChenXinyu WangJieshou LiWeiwei DingNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-9 (2021)
institution DOAJ
collection DOAJ
language EN
topic Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Cytology
QH573-671
spellingShingle Neoplasms. Tumors. Oncology. Including cancer and carcinogens
RC254-282
Cytology
QH573-671
Zehua Duan
Tian Xie
Chengnan Chu
Fang Chen
Xinyu Wang
Jieshou Li
Weiwei Ding
De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis
description Abstract 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.
format article
author Zehua Duan
Tian Xie
Chengnan Chu
Fang Chen
Xinyu Wang
Jieshou Li
Weiwei Ding
author_facet Zehua Duan
Tian Xie
Chengnan Chu
Fang Chen
Xinyu Wang
Jieshou Li
Weiwei Ding
author_sort Zehua Duan
title De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis
title_short De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis
title_full De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis
title_fullStr De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis
title_full_unstemmed De-escalation antibiotic therapy alleviates organ injury through modulation of NETs formation during sepsis
title_sort de-escalation antibiotic therapy alleviates organ injury through modulation of nets formation during sepsis
publisher Nature Publishing Group
publishDate 2021
url https://doaj.org/article/591756b817a645679e99147ab43f9efa
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