氧化白蛋白通过p38 MAP激酶在白细胞中引发细胞因子风暴：在

StephenW

Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis
José Alcaraz‐Quiles
Mireia Casulleras
Karl Oettl
Esther Titos
Roger Flores‐Costa
Marta Duran‐Güell
Cristina López‐Vicario
Marco Pavesi
Rudolf E. Stauber
Vicente Arroyo
Joan Clària
First published: 02 August 2018
https://doi.org/10.1002/hep.30135

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.30135


Abstract

Decompensated cirrhosis is characterized by exuberant systemic inflammation. Although the inducers of this feature remain unknown, the presence of circulating forms of oxidized albumin, namely human non‐mercaptalbumin 1 (HNA1) and 2 (HNA2) is a common finding in cirrhosis. The aim of this study was to explore the ability of these oxidized albumin forms to induce systemic inflammation by triggering the activation of peripheral leukocytes. We observed significantly higher plasma levels of HNA1 and HNA2 in cirrhotic patients (n=256) as compared to healthy volunteers (n=48), levels that gradually increased during the course from compensated to decompensated to ACLF. Plasma HNA1 and HNA2 levels significantly correlated with inflammatory markers (i.e. IL‐6, IL‐1β, TNF‐α and IL‐8) in cirrhotic patients. To test directly the inflammatory effects of HNA1 and HNA2 on leukocytes, these oxidized albumin forms were prepared ex vivo and their post‐translational modifications monitored by LC‐qTOF/MS. HNA1, but not HNA2, at concentrations seen in patients with decompensated cirrhosis, increased IL‐1β, IL‐6 and TNF‐α mRNA and protein expression in leukocytes from both healthy volunteers and cirrhotic patients. Moreover, HNA1 up‐regulated the expression of eicosanoid‐generating enzymes (i.e. COX‐2 and mPGES‐1) and the production of inflammatory eicosanoids (PGE2, PGF2α, TXB2 and LTB4), as determined by LC‐ESI‐MS/MS. The inflammatory response to HNA1 was more pronounced in peripheral blood mononuclear cells (PBMC) and marginal in polymorphonuclear neutrophils (PMN). Kinome analysis of PBMC revealed that HNA1 induced the phosphorylation of p38 MAP kinase, the inhibition of which blocked HNA1‐induced cytokine and COX‐2 induction. Conclusion: HNA1 triggers an inflammatory response in PBMC, providing a rationale for its removal and replacement by reduced albumin in the prevention of systemic inflammation in patients with advanced liver disease.

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StephenW

氧化白蛋白通过p38 MAP激酶在白细胞中引发细胞因子风暴：在失代偿期肝硬化中全身炎症中的作用
JoséAlcaraz-Quiles
Mireia Casulleras
Karl Oettl
以斯帖提多
罗杰弗洛雷斯 - 科斯塔
Marta Duran-Güell
CristinaLópez-Vicario
Marco Pavesi
Rudolf E. Stauber
维森特阿罗约
琼·克拉里亚
首次发表：2018年8月2日
https://doi.org/10.1002/hep.30135

本文已被接受发布并经过完整的同行评审，但尚未通过编辑，排版，分页和校对过程，这可能导致此版本与记录版本之间存在差异。请引用本文为doi：10.1002 / hep.30135


抽象

失代偿性肝硬化的特征在于旺盛的全身性炎症。尽管该特征的诱导剂仍然未知，但是存在循环形式的氧化白蛋白，即人非巯基白蛋白1（HNA1）和2（HNA2）是肝硬化中的常见发现。该研究的目的是探索这些氧化白蛋白形式通过触发外周白细胞的活化来诱导全身性炎症的能力。与健康志愿者（n = 48）相比，我们在肝硬化患者（n = 48）中观察到HNA1和HNA2的血浆水平显着升高，在从补偿到失代偿至ACLF的过程中逐渐增加。血浆HNA1和HNA2水平与肝硬化患者的炎症标志物（即IL-6，IL-1β，TNF-α和IL-8）显着相关。为了直接测试HNA1和HNA2对白细胞的炎症作用，离体制备这些氧化的白蛋白形式，并通过LC-qTOF / MS监测它们的翻译后修饰。 HNA1，但不是HNA2，在失代偿性肝硬化患者中观察到的浓度，来自健康志愿者和肝硬化患者的白细胞中IL-1β，IL-6和TNF-αmRNA和蛋白质表达增加。此外，通过LC-ESI-MS / MS测定，HNA1上调产生类花生酸的酶（即COX-2和mPGES-1）的表达和炎性类二十烷酸（PGE2，PGF2α，TXB2和LTB4）的产生。 HNA1的炎症反应在外周血单核细胞（PBMC）中更明显，在多形核中性粒细胞（PMN）中更为明显。 PBMC的Kinome分析显示HNA1诱导p38 MAP激酶的磷酸化，其抑制阻断HNA1诱导的细胞因子和COX-2诱导。结论：HNA1在PBMC中引发炎症反应，为晚期肝病患者预防全身炎症中白蛋白的去除和替代提供了理论基础。

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