RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock.


  • 影响因子:4.63
  • DOI:10.1136/thoraxjnl-2019-213613
  • 作者列表:"Zhang K","Jin Y","Lai D","Wang J","Wang Y","Wu X","Scott M","Li Y","Hou J","Billiar T","Wilson M","Shu Q","Fang X","Fan J
  • 发表时间:2020-03-01

BACKGROUND:Type 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated. OBJECTIVE:To investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model. METHODS:Circulating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well. RESULTS:The number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS. CONCLUSIONS:These results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.


背景: 2型免疫功能紊乱导致失血性休克 (HS) 和创伤后的急性肺损伤和死亡。第2组固有淋巴样细胞 (ILC2s) 在调节2型免疫应答中起重要作用。然而,ILC2在HS后急性肺损伤中的作用和潜在机制尚未阐明。 目的: 探讨ILC2s在HS诱导的急性肺损伤中的调节作用及其机制。 方法: 对HS患者和健康对照的2型免疫反应的循环标志物进行表征。使用HS的小鼠模型,确定了高迁移率族蛋白b1 (HMGB1)-晚期糖基化终产物受体 (RAGE) 信号在ILC2增殖、存活和功能调节中的作用。并评估ILC2在诱导2型免疫功能障碍中的作用。 结果: HS患者循环中ILC2s的数量显著增加,这与患者2型免疫反应标志物的增加相关。动物研究表明,HMGB1通过RAGE通过促进ILC2增殖和减少ILC2死亡来诱导ILC2在肺中的积累。ILC2s的扩张导致2型细胞因子分泌和肺内嗜酸性粒细胞浸润,这两者均导致HS后肺损伤。 结论: 这些结果表明HMGB1-RAGE信号在调节ILC2生物学功能中起关键作用,ILC2生物学功能加重HS后的2型肺部炎症。



作者列表:["Williams J","Merutka N","Meyer D","Bai Y","Prater S","Cabrera R","Holcomb JB","Wade CE","Love JD","Cotton BA"]

METHODS:PURPOSE:Following US military implementation of a cold-stored whole blood program, several US trauma centers have begun incorporating uncrossmatched, group O cold-stored whole blood into civilian trauma resuscitation. We set out to evaluate the safety profile, transfusion reactions events, and impact of low-titer group O whole blood (LTO-WB) at our center. METHODS:In November 2017, we added LTO-WB to each of our helicopters and to our emergency department (ED) refrigerator, alongside that of existing red blood cells and plasma. We collected information on all patients with trauma receiving prehospital or ED transfusion of uncrossed, emergency release blood products between November 2017 and June 2018. Patients were divided into those receiving any LTO-WB and those receiving only red blood cell and or plasma (COMP). Serial hemolysis panels were obtained at 3 hours, 24 hours, and 48 hours. All data were run using STATA 12.1. Statistical significance was set at p < 0.05. RESULTS:One hundred ninety-eight patients received LTO-WB and 152 patients received COMP. There were no differences in age, sex, or mechanism. The LTO-WB patients had higher chest Abbreviated Injury Scale scores (median, 3 vs. 2; p = 0.027), as well as worse arrival base excess (median, -7 vs. -5; p = 0.014) and lactate (5.1 vs. 3.5; p < 0.001). The LTO-WB patients received less post-ED blood products than the COMP patients (median, 0 vs. 3; p = 0.001). There was no difference in survival (LTO-WB, 73%; COMP, 74%; p = 0.805). There were only two suspected transfusion reactions, both in the COMP group (p = 0.061). There was no difference in hemolysis panel values. Controlling for age, severity of injury, and prehospital physiology, LTO-WB was associated with a 53% reduction in post-ED blood product transfusion (odds ratio, 0.47; 0.23-0.94 95% CI; p = 0.033) and two-fold increase in likelihood of survival (odds ratio, 2.19; 1.01-4.76 95% CI; p = 0.047). CONCLUSION:Low-titer group O whole blood has similar evidence of laboratory hemolysis, similar transfusion reaction rates, and is associated with a reduction in post-ED transfusions and increase likelihood of survival. LEVEL OF EVIDENCE:Therapeutic, Level II.

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作者列表:["Chayer B","Allard L","Qin Z","Garcia-Duitama J","Roger L","Destrempes F","Cailhier JF","Denault A","Cloutier G"]

METHODS:BACKGROUND:An enhanced inflammatory response is a trigger to the production of blood macromolecules involved in abnormally high levels of erythrocyte aggregation. OBJECTIVE:This study aimed at demonstrating for the first time the clinical feasibility of a non-invasive ultrasound-based erythrocyte aggregation quantitative measurement method for potential application in critical care medicine. METHODS:Erythrocyte aggregation was evaluated using modeling of the backscatter coefficient with the Structure Factor Size and Attenuation Estimator (SFSAE). SFSAE spectral parameters W (packing factor) and D (mean aggregate diameter) were measured within the antebrachial vein of the forearm and tibial vein of the leg in 50 healthy participants at natural flow and reduced flow controlled by a pressurized bracelet. Blood samples were also collected to measure erythrocyte aggregation ex vivo with an erythroaggregometer (parameter S10). RESULTS:W and Din vivo measurements were positively correlated with the ex vivoS10 index for both measurement sites and shear rates (correlations between 0.35-0.81, p < 0.05). Measurement at low shear rate was found to increase the sensitivity and reliability of this non-invasive measurement method. CONCLUSIONS:We behold that the SFSAE method presents systemic measures of the erythrocyte aggregation level, since results on upper and lower limbs were highly correlated.

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作者列表:["Takeshita S","Tanaka KA","Sawa T","Sanda M","Mizobe T","Ogawa S"]

METHODS:BACKGROUND:Incomplete reversal with a recommended 5-g dose of idarucizumab has been reported in patients with excessively high dabigatran concentrations. A timely detection of reversal failure after idarucizumab using whole blood (WB) coagulation testing is clinically useful. The aims of this study were to determine residual dabigatran activity after idarucizumab on thrombin generation (TG) using in vitro supratherapeutic dabigatran models and to compare 4 WB point-of-care tests (activated partial thromboplastin time [aPTT], prothrombin time [PT], and 2 thromboelastometry tests) with the TG results. METHODS:Blood samples from 12 healthy volunteers were spiked in vitro with 0-5000 ng/mL of dabigatran. Dabigatran reversal was evaluated by adding 1000 μg/mL of idarucizumab (Praxbind) to dabigatran-spiked samples, which reflect the administration of 5-g idarucizumab to a 70-kg patient. Residual dabigatran activity was assessed using the calibrated automated TG (Thrombinoscope) in platelet-poor plasma samples. The TG results were compared with WB aPTT (DRIHEMATO APTT-S) and PT (DRIHEMATO PT-S) using CG02N analyzer, thromboelastometry (ROTEM) triggered by ellagic acid (INTEM) and tissue factor (EXTEM). RESULTS:At a therapeutic concentration of dabigatran (200 ng/mL), the lag time was prolonged, and peak TG was decreased. The effects of dabigatran on TG were increased up to 1000 ng/mL, and TG was obliterated at higher supratherapeutic dabigatran levels (P < .001 versus control, respectively). TG was fully restored with idarucizumab when dabigatran was ≤2000 ng/mL, but residual anticoagulant activity was observed at higher dabigatran levels. Dabigatran prolonged WB aPTT and PT concentration dependently, and residual prolongations were observed when idarucizumab was added to 3000 or 5000 ng/mL of dabigatran (P < .001 versus control, respectively). In contrast, both INTEM and EXTEM clotting times were reversed toward reference ranges at all dabigatran concentrations when idarucizumab was added. CONCLUSIONS:Our data indicate that the recommended dose of idarucizumab may not restore TG completely with excessively elevated concentrations of dabigatran. All WB measurements with aPTT, PT, and thromboelastometry predicted supratherapeutic dabigatran concentrations, whereas those tests varied in sensitivity to residual anticoagulant activity after reversal. WB aPTT corresponded well with plasma TG changes among those measurements, but the use of thromboelastometry may overestimate the effect of idarucizumab. Caution should be exercised before extrapolating in vitro point-of-care data to the clinical monitoring of dabigatran reversal.

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