Alcoholic hepatitis Cirrhosis Infection Interleukin-33 Migration Polymorphonuclear neutrophils
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摘要

BACKGROUND & AIMS:Severe alcoholic hepatitis (SAH) is associated with a high risk of infection. The IL-33/ST2 pathway is involved in sepsis control but data regarding its role in alcohol-related liver disease (ALD) are lacking. We aimed to characterize the role of IL-33/ST2 in the polymorphonuclear neutrophils (PMNs) of patients with ALD and SAH.
METHODS:Serum and circulating neutrophils were collected from patients with SAH, alcoholic cirrhosis and healthy controls. We quantified IL-33/ST2 pathway activity and CXCR2 at baseline and after exposure to IL-33. We also determined the migration capacity of PMNs.
RESULTS:The decoy receptor of IL-33 (soluble ST2 [sST2]) was increased in SAH vs. cirrhosis and controls, demonstrating the defect in this pathway during ALD. The sST2 level was associated with response to treatment, 2-month survival, infection-free survival and probability of infection in SAH. Endotoxemia was weakly correlated with sST2. GRK2, a negative regulator of CXCR2, was overexpressed in PMNs of patients with SAH and cirrhosis and was decreased by IL-33. CXCR2 levels on PMNs were lower in SAH vs. cirrhosis and controls. Treatment with IL-33 partially restored CXCR2 expression in SAH and cirrhosis. PMN migration upon IL-8 was lower in patients with SAH and cirrhosis vs. controls. Treatment with IL-33 partially restored migration in those with SAH and cirrhosis. Interestingly, the migration capacity of PMNs and the response to IL-33 were enhanced in responders to corticosteroids (Lille <0.45) compared to non-responders.
CONCLUSION:The IL33/ST2 pathway is defective in SAH and predicts outcome. This defect is associated with decreased CXCR2 expression on the surface of PMNs and lower migration capacity, which can be corrected by IL-33, especially in patients responding to steroids. These results suggest that IL-33 has therapeutic potential for SAH and its infectious complications.
LAY SUMMARY:The neutrophils of patients with severe alcoholic hepatitis are associated with a defect in the IL-33/ST2 pathway. This defect is associated with lower migration capacities in neutrophils and a higher probability of getting infected. Administration of IL-33 to the neutrophils at least partly restores this defect and may be effective at reducing the risk of infection in patients with severe alcoholic hepatitis.

译文

背景与目的: 重度酒精性肝炎 (SAH) 与感染的高风险相关。IL-33/ST2 通路参与败血症控制,但缺乏关于其在酒精相关肝病 (ALD) 中的作用的数据。我们旨在描述 IL-33/ST2 在 ALD 和 SAH 患者多形核中性粒细胞 (PMNs) 中的作用。
方法: 收集 SAH 患者、酒精性肝硬化患者和健康对照者的血清和循环中性粒细胞。我们在基线和暴露于 IL-33 后定量了 IL-33/ST2 通路活性和 CXCR2。我们还确定了 PMNs 的迁移能力。
结果: SAH 与肝硬化和对照组相比,IL-33 的诱饵受体 (可溶性 ST2 [sST2]) 增加,表明 ALD 期间该通路存在缺陷。SST2 水平与 SAH 的治疗反应、 2 个月生存率、无感染生存率和感染概率相关。内毒素血症与 sst2 弱相关。GRK2 是 CXCR2 的负调控因子,在 SAH 和肝硬化患者的 PMNs 中过表达,并下降了 IL-33。在 SAH 与肝硬化和对照组中,PMNs 上的 CXCR2 水平较低。IL-33 治疗部分恢复了 SAH 和肝硬化中 CXCR2 的表达。与对照组相比,SAH 和肝硬化患者 IL-8 时 PMN 迁移较低。IL-33 治疗部分恢复了 SAH 和肝硬化患者的迁移。有趣的是,与无反应者相比,皮质类固醇反应者的 PMNs 迁移能力和 IL-33 反应增强 (里尔 <0.45)。
结论: IL33/ST2 通路在 SAH 中存在缺陷,并可预测预后。这种缺陷与 PMNs 表面 CXCR2 表达减少和迁移能力降低有关,这可以通过 IL-33 来纠正,特别是在对类固醇有反应的患者中。这些结果表明 IL-33 对 SAH 及其感染性并发症具有治疗潜力。
总结: 重度酒精性肝炎患者的中性粒细胞与 IL-33/ST2 通路的缺陷有关。这种缺陷与中性粒细胞的迁移能力较低和感染的概率较高有关。对中性粒细胞施用 IL-33 至少部分恢复了这一缺陷,并可能有效降低重度酒精性肝炎患者的感染风险。

severe alcoholic hepatitis

消化 肝炎 疾病
概述  :  

重症酒精性肝炎是酒精性肝炎( alcoholic hepatitis,AH)的严重类型,重症酒精性肝炎患者通常是重度饮酒者,伴有迅速黄疸、乏力、厌食、疼痛性肝肿大和SIRS等特点,如果治疗不及时,短期生存率较低。最近,美国国立卫生院酒精滥用与成瘾研究所(NAAA)酒精性肝炎联盟共识声明中AH的定义如下:酒精摄入>50g/d,持续至少6个月,60d内出现黄疸(血清胆红素>3mg/dl),AST增高(50~400/L)以及AST/ALT>1.5,此外无其他明显导致肝炎的因素

severe 英 /sɪˈvɪə(r)/  美 /sɪˈvɪr/

释义   adj. 严峻的;严厉的;剧烈的;苛刻的

例句   Of course, if you already have severe depressive symptoms, then seek help right away. 当然,如果你已经有严重的抑郁症状,应该马上寻求帮助。

 

alcoholic 英 /ˌælkəˈhɒlɪk/  美 /ˌælkəˈhɑːlɪk/

释义   adj. 酒精的,含酒精的

n. 酒鬼,酗酒者

例句   He escapes from his abusive, alcoholic father by faking his own murder and heading off on his own. 为了逃离酗酒和虐待他的父亲,哈克假造自己被谋杀,然后独自离家出走。

 

hepatitis  英 /ˌhepəˈtaɪtɪs/  美 /ˌhepəˈtaɪtɪs/

释义   n. 肝炎

例句   BACKGROUND&AIM: To explore human Hapatitis B virus(HBV)gene integrated into the genome of the housefly. 背景与目的:探讨人乙肝病毒基因能否整合在家蝇基因组中。

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