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
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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.
This article is protected by copyright. All rights reserved. 作者: StephenW 时间: 2018-8-9 16:12
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