Early intravenous administration of tranexamic acid ameliorates intestinal barrier injury induced by neutrophil extracellular traps in a rat model of trauma/hemorrhagic shock

Chu, Chengnan; Yang, Chao; Wang, Xinyu; Xie, Tian; Sun, Shilong; Liu, Fei; Wang, Kai; Duan, Zhiwen; Ding, Weiwei; Li, Jieshou

doi:10.1016/j.surg.2019.10.009

Cited by 27 publications

(32 citation statements)

References 41 publications

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“…Current studies have shown that NETs and their elements can cause organ injury, coagulation disorders, autoimmune diseases, and thromboembolism [ 19 ]. Although NETs are a double-edged sword in sepsis, few studies have focused on their antibacterial function in the early stage of sepsis, during which NETs can trap pathogens and prevent bacterial dissemination [ 17 , 20 , 21 ]. Our data show clearing NETs with DNase I will increase organ damage, these results prove that NETs formation plays an important role in organ protection during the early stage of sepsis.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Current studies have shown that NETs and their elements can cause organ injury, coagulation disorders, autoimmune diseases, and thromboembolism [20]. Although NETs are a double-edged sword in sepsis, few studies have focused on their antibacterial function in the early stage of sepsis, during which NETs can trap pathogens and prevent bacterial dissemination [17,18,21]. Our data show clearing NETs with DNaseI will lead to the spread of infection and increased organ damage, these results prove that NETs formation playing an important role in organ protection during the early stage of sepsis.…”

Section: Discussionmentioning

confidence: 99%

“…NET quantification was performed as previously described (18). In brief, the cells were seeded at 5.2 × 10ˆ4 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: Net Quantification and Ros Detectionmentioning

confidence: 99%

De-escalation Antibiotic Therapy Alleviates Organ Injury through Modulation of NET Formation during Sepsis

Xie¹,

Chu²,

Sun³

et al. 2020

Preprint

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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 detail mechanisms of de-escalation strategy are still unclear. Here we hypothesized neutrophil extracellular trap (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 based on their effects on NETs formation in CLP model. Organ injury, inflammatory cytokines, NETs levels were compared and evaluated. The in vitro study showed that imipenem and ceftriaxone had opposite effects on NETs formation in activated neutrophils. De-escalation therapy resulted in an evaluated MPO-DNA during early stage and decreased MPO-DNA during late stage, which exerted the reverse effects in escalation therapy sepsis animal model. Inflammatory response and organ injury exacerbated when eliminated NETs with DNAseI during 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). We 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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“…It was demonstrated that DNase I treatment could ameliorate tissue injury, apoptosis, and oxidative stress in the intestine [ 88 ]. In a rat model of trauma/hemorrhagic shock, early intravenous tranexamic acid administration attenuated NET formation and prevented disruption of tight junction protein [ 90 ]. These data indicate that NETs play a detrimental role in the pathogenesis of intestinal barrier during intestinal IRI.…”

Section: Nets In Intestinal Irimentioning

confidence: 99%

Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology

Chen

Shao

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Many gut disease etiologies are attributed to the presence of robust inflammatory cell recruitment. The recruitment of neutrophils plays a vital role in inflammatory infiltration. Neutrophils have various antimicrobial effector mechanisms, including phagocytosis, oxidative burst, and degranulation. It is suggested that neutrophils could release neutrophil extracellular traps (NETs) to kill pathogens. However, recent evidence indicates that neutrophil infiltration within the gut is associated with disrupted local immunological microenvironment and impaired epithelial barrier. Growing evidence implies that NETs are involved in the progression of many diseases, including cancer, diabetes, thrombosis, and autoimmune disease. Increased NET formation was found in acute or chronic conditions, including infection, sterile inflammation, cancer, and ischemia/reperfusion injury (IRI). Here, we present a comprehensive review of recent advances in the understanding of NETs, focusing on their effects in gut disease. We also discuss NETs as a potential therapeutic target in gut disease.

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Early intravenous administration of tranexamic acid ameliorates intestinal barrier injury induced by neutrophil extracellular traps in a rat model of trauma/hemorrhagic shock

Cited by 27 publications

References 41 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

De-escalation Antibiotic Therapy Alleviates Organ Injury through Modulation of NET Formation during Sepsis

Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology

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