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首页> 外文会议>World biomaterials congress >Evaluation of an intetieukin-8 conjugated extracorporeal neutrophil reprogramming device for the treatment of acute inflammatory disorders
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Evaluation of an intetieukin-8 conjugated extracorporeal neutrophil reprogramming device for the treatment of acute inflammatory disorders

机译：Intetieukin-8缀合的体外嗜中性粒细胞重编程设备对急性炎症性疾病治疗的评估

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Introduction: As one of the first responders to sites of inflammation, neutrophils play a critical role in the progression of acute inflammatory conditions such as sepsis. High quantities of neutrophils migrating to remote organs such as the lungs has been associated with increased morbidity and mortality by initiating multiple organ dysfunction or immune paralysis in septic patients. The migration and activation of neutrophils is regulated by CXCR-1 and CXCR-2, g-protein coupled receptors that bind to interieukin-8 (CXCL-8). It is hypothesized that exposure to high levels of immobilized CXCL-8 within an extracorporeal device will attenuate neutrophil migratory response. In this study, a method for immobilization of CXCL-8 on the inner lumen of AN69 dialyzer fibers was developed and constructed into a prototype extracorporeal device. Additionally, the device was evaluated by measuring CXCR-1 and CXCR-2 neutrophil surface receptor expression after human blood perfusion. Materials and Methods: First, amine modified AN69 dialyzer fibers (Gambro) were potted into a polycarbonate housing. Module ends were trimmed to open the fiber inner lumen. An NHS activated polyethylene-glycol spacer was immobilized on the inner lumen. CXCL-8 was then conjugated using NHS/EDC linkage. A control module used bovine serum albumin in place of CXCL-8. Fresh human whole blood was recirculated through the device for 90 minutes. A positive control was created by adding 1 μg/ml soluble CXCL-8 to whole blood. Blood samples were collected at 45 and 90 minutes for analysis of CXCR-1 and CXCR-2 expression using flow cytometry. indicating complete migratory shutoff. In the CXCL-8 modified module, neutrophil surface receptor expression of CXCR-1 and CXCR-2 decreased by 50% and 90%. CXCR-2 downregulation in this module closely tracked the positive control, indicating change in neutrophil migratory phenotype. The BSA modified control module induced less than 10% variation from baseline blood, demonstrating downregulation in the CXCL-8 module was due to the immobilized chemokine. Conclusion: An effective method for immobilization of CXCL-8 on the inner lumen of AN69 dialyzer fibers was developed. Furthermore, the CXCL-8 modified prototype module induced downregulation of CXCR-1 and CXCR-2 neutrophil surface receptors when perfused with human whole blood. Functionally, it is anticipated that CXCR-1 and CXCR-2 of reprogrammed neutrophils to a chemotactic gradient.
机译：简介：中性粒细胞是对炎症部位的首批响应者之一，在急性炎症条件（如败血症）的进程中起着至关重要的作用。大量的嗜中性粒细胞迁移至败血症患者的多器官功能障碍或免疫麻痹，与发病率和死亡率增加有关，这些肺嗜中性粒细胞迁移到诸如肺等偏远器官。中性粒细胞的迁移和激活受CXCR-1和CXCR-2（与白细胞介素8（CXCL-8）结合的g蛋白偶联受体）调节。假设在体外装置中暴露于高水平的固定化CXCL-8会减弱中性粒细胞的迁徙反应。在这项研究中，开发了一种将CXCL-8固定在AN69透析器纤维内腔上的方法，并将其构建为原型体外装置。此外，通过在人血灌注后测量CXCR-1和CXCR-2中性粒细胞表面受体的表达来评估该设备。材料和方法：首先，将胺改性的AN69透析纤维（Gambro）装入聚碳酸酯外壳中。修剪模块末端以打开光纤内部管腔。 NHS活化的聚乙二醇间隔基固定在内腔上。然后使用NHS / EDC联结缀合CXCL-8。对照模块使用牛血清白蛋白代替CXCL-8。新鲜的人类全血通过该设备再循环90分钟。通过向全血中添加1μg/ ml可溶性CXCL-8来创建阳性对照。在第45和90分钟时收集血样，使用流式细胞仪分析CXCR-1和CXCR-2的表达。表示完全关闭了迁移。在CXCL-8修饰模块中，CXCR-1和CXCR-2的嗜中性粒细胞表面受体表达分别降低了50％和90％。该模块中的CXCR-2下调密切跟踪阳性对照，表明中性粒细胞迁移表型发生了变化。 BSA修饰的控制模块引起的基线血液变化少于10％，表明CXCL-8模块的下调是由于固定化趋化因子引起的。结论：开发了一种将CXCL-8固定在AN69透析纤维内腔上的有效方法。此外，当用人全血灌注时，CXCL-8修饰的原型模块诱导了CXCR-1和CXCR-2中性粒细胞表面受体的下调。在功能上，预期重编程的嗜中性粒细胞的CXCR-1和CXCR-2达到趋化梯度。

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