Antithrombin III improved neutrophil extracellular traps in lung after the onset of endotoxemia

Ishikawa, Michiko; Yamashita, Hayato; Oka, Nobuki; Ueda, Takahiro; Kohama, Kazuyuki; Nakao, Atsunori; Kotani, Joji

doi:10.1016/j.jss.2016.09.041

Cited by 21 publications

(24 citation statements)

References 28 publications

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“…Again, in rat models less tissue destruction of the pulmonary vessels was detected after antithrombin administration following LPS-induced sepsis, which was attributed to the ability of antithrombin to induce prostacyclin release and thereby reduce leukocyte activation ( Uchiba & Okajima, 1997 ). In another rat model treatment of pneumonia, triggered by S. pneumoniae, with antithrombin resulted in a marked reduction in neutrophil cells in the lung, decreased levels of pro-inflammatory cytokines, and a reduction in NET (neutrophil extracellular trap) formation ( Ishikawa et al., 2017 ; Choi et al., 2008 ). Here, too, a reduction in lung tissue destruction as well as a significant reduction in colony formation of S. pneumoniae was demonstrated ( Choi et al., 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Antithrombin deficiency is associated with mortality and impaired organ function in septic pediatric patients: a retrospective study

Niederwanger

Hell

Hofer

et al. 2018

PeerJ

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BackgroundSepsis remains a major problem in intensive care medicine. It is often accompanied by coagulopathies, leading to thrombotic occlusion of small vessels with subsequent organ damage and even fatal multi-organ failure. Prediction of the clinical course and outcome—especially in the heterogeneous group of pediatric patients—is difficult. Antithrombin, as an endogenous anticoagulant enzyme with anti-inflammatory properties, plays a central role in controling coagulation and infections. We investigated the relationship between antithrombin levels and organ failure as well as mortality in pediatric patients with sepsis.MethodsData from 164 patients under the age of 18, diagnosed with sepsis, were retrospectively reviewed. Antithrombin levels were recorded three days before to three days after peak C-reactive protein to correlate antithrombin levels with inflammatory activity. Using the concept of developmental haemostasis, patients were divided into groups <1 yr and ≥1 yr of age.ResultsIn both age groups, survivors had significantly higher levels of antithrombin than did deceased patients. An optimal threshold level for antithrombin was calculated by ROC analysis for survival: 41.5% (<1 yr) and 67.5% (≥1 yr). The mortality rate above this level was 3.3% (<1 yr) and 9.5% (≥1 yr), and below this level 41.7% (<1 yr) and 32.2% (≥1 yr); OR 18.8 (1.74 to 1005.02), p = 0.0047, and OR 4.46 (1.54 to 14.89), p = 0.003. In children <1 yr with antithrombin levels <41.5% the rate of respiratory failure (66.7%) was significantly higher than in patients with antithrombin levels above this threshold level (23.3%), OR 6.23 (1.23 to 37.81), p = 0.0132. In children ≥1 yr, both liver failure (20.3% vs 1.6%, OR 15.55 (2.16 to 685.01), p = 0.0008) and a dysfunctional intestinal tract (16.9% vs 4.8%, OR 4.04 (0.97 to 24.08), p = 0.0395) occurred more frequently above the antithrombin threshold level of 67.5%.ConclusionIn pediatric septic patients, significantly increased mortality and levels of organ failure were found below an age-dependent antithrombin threshold level. Antithrombin could be useful as a prognostic marker for survival and occurrence of organ failure in pediatric sepsis.

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Section: Discussionmentioning

confidence: 99%

Antithrombin deficiency is associated with mortality and impaired organ function in septic pediatric patients: a retrospective study

Niederwanger

Hell

Hofer

et al. 2018

PeerJ

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“…Anticoagulant therapy, including antithrombin, recombinant thrombomodulin (rTM), and protease inhibitor supplementation, is strongly recommended in the Japanese guidelines for management of DIC [ 45 , 46 ], and these therapies may affect the formation of NETs. Recently, administration of antithrombin was reported to reduce NET formation in the lungs during lipopolysaccharide (LPS)-induced endotoxemia [ 47 ]. Serine protease inhibitors [ 48 ] and rTM [ 49 ] are also known to inhibit formation of NETs in vitro.…”

Section: Discussionmentioning

confidence: 99%

Plasma myeloperoxidase-conjugated DNA level predicts outcomes and organ dysfunction in patients with septic shock

et al. 2018

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BackgroundRecent studies have suggested that excessive formation of neutrophil extracellular traps (NETs) plays a critical role in the pathogenesis of sepsis. Although elevation of the plasma level of cell-free DNA (cf-DNA) has been reported in sepsis patients, there has been little direct measurement of circulating free NETs such as myeloperoxidase-conjugated DNA (MPO-DNA). The objectives of this study were to detect NETs in the bloodstream of patients with septic shock, and to assess the correlations of circulating NET levels with organ dysfunction, disease severity, and mortality.MethodsFifty-five patients with septic shock admitted to the intensive care units (ICUs) of 35 Japanese hospitals were studied. Septic shock was diagnosed according to the 1997 definition of the American College of Chest Physicians/Society of Critical Care Medicine. To detect circulating NETs, plasma levels of MPO-DNA and cf-DNA were measured by sandwich enzyme-linked immunosorbent assay and by fluorometric assay on days 1, 3, and 7 after the onset of septic shock. Physiological and mortality data were collected from the clinical database.ResultsOn days 1, 3, and 7, the patients showed a marked increase in plasma MPO-DNA levels compared with healthy volunteers, whereas the plasma cf-DNA level was only increased significantly on day 1 and then decreased rapidly. A high MPO-DNA level on days 3 and 7 were associated with 28-day mortality.On days 3 and 7, the MPO-DNA levels were inversely correlated with both the mean arterial pressure and the PaO2/FIO2 ratio, whereas the cf-DNA level was not correlated with either parameter. There was a positive correlation between the plasma MPO-DNA level and the sepsis-related organ failure assessment score on days 3 and 7. Neither cf-DNA nor MPO-DNA levels were correlated with the disseminated intravascular coagulation (DIC) score or the platelet count.ConclusionThe increase in circulating MPO-DNA in patients with septic shock indicates acceleration of NET formation in the early stages of sepsis. High MPO-DNA levels are associated with the severity of organ dysfunction and 28-day mortality due to septic shock, but not with the DIC score. These results suggest that excessive NET formation contributes to the pathogenesis of septic shock.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2109-7) contains supplementary material, which is available to authorized users.

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“…3D , this delayed treatment significantly enhanced the percentage survival against lethal endotoxemia compared with LPS+saline alone; however, this protective effect was reversed with HMGB1 injection via tail vein (2 µg/mouse; followed at 48 h after LPS). In addition, treatment of mice with PBX3 siRNA beginning at 3 h following LPS injection, which was defined as the onset of endotoxemia ( 20 ), significantly attenuated the systemic release of HMGB1 measured at 32 h. (P<0.01; Fig. 3E ).…”

Section: Resultsmentioning

confidence: 91%

“…4A ). As endothelial membrane barriers maybe disrupted by LPS induction ( 20 ), HUVECs were infected with Lenti-PBX3-shRNA for 24 h following LPS treatment (100 ng/ml). Results indicated that PBX3 knockdown significantly attenuated the LPS-mediated membrane disruption (P<0.01; Fig.…”

Section: Resultsmentioning

confidence: 99%

Pre-B cell leukemia transcription factor 3 induces inflammatory responses in human umbilical vein endothelial cells and murine sepsis via acting a competing endogenous RNA for high mobility group box 1 protein

et al. 2018

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The present study investigated the roles of pre-B cell leukemia transcription factor 3 (PBX3) in sepsis. Reverse transcription-quantitative polymerase chain reaction and western blot analysis indicated that overexpression of the PBX 3′-untranslated region (UTR) promoted high mobility group box 1 (HMGB1) protein expression in human umbilical vein endothelial cells (HUVECs) (P<0.01). Furthermore, post-treatment of PBX3 small interfering (si)RNA suppressed lipopolysaccharide (LPS)-mediated HMGB1 release and attenuated HMGB1-mediated hyperpermeability and leukocyte migration in HUVECs and septic mice (P<0.01). Additionally, post-injection of PBX3 siRNA also induced the downregulation of cecal ligation and puncture-induced HMGB1 release, production of IL-6 and mortality (P<0.01). Mechanistically, the 3′UTRs of PBX3 and HMGB1 were identified to harbor six common micro (mi)RNA binding sites, and PBX 3′UTR increased HMGB1 expression in a 3′UTR- and miRNA-dependent manner. Notably, the coding sequence of PBX3 did not increase HMGB1 expression in HUVECs. Collectively, the present study indicates that PBX 3′UTR may induce inflammatory responses and sepsis via acting as a competing endogenous RNA for HMGB1.

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Antithrombin III improved neutrophil extracellular traps in lung after the onset of endotoxemia

Cited by 21 publications

References 28 publications

Antithrombin deficiency is associated with mortality and impaired organ function in septic pediatric patients: a retrospective study

Antithrombin deficiency is associated with mortality and impaired organ function in septic pediatric patients: a retrospective study

Plasma myeloperoxidase-conjugated DNA level predicts outcomes and organ dysfunction in patients with septic shock

Pre-B cell leukemia transcription factor 3 induces inflammatory responses in human umbilical vein endothelial cells and murine sepsis via acting a competing endogenous RNA for high mobility group box 1 protein

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