Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/130318
Title: Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
Author: Alcaraz-Quiles, José
Casulleras, Mireia
Oettl, Karl
Titos Rodríguez, Esther
Flores Costa, Roger
Duran Güell, Marta
López-Vicario, Cristina
Pavesi, Marco
Stauber, Rudolf E.
Arroyo, Vicente
Clària i Enrich, Joan
Keywords: Cirrosi hepàtica
Inflamació
Leucòcits
Hepatic cirrhosis
Inflammation
Leucocytes
Issue Date: Nov-2018
Publisher: Wiley
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 nonmercaptalbumin 1 (HNA1) and 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 patients with cirrhosis (n = 256) compared to healthy volunteers (n = 48), which gradually increased during the course from compensated to decompensated to acute-on-chronic liver failure. Plasma HNA1 and HNA2 levels significantly correlated with inflammatory markers (i.e., interleukin-6 [IL-6], IL-1β, tumor necrosis factor-alpha [TNF-α] and IL-8) in patients with cirrhosis. To directly test the inflammatory effects of HNA1 and HNA2 on leukocytes, these oxidized albumin forms were prepared ex vivo and their posttranslational modifications monitored by liquid chromatography (LC)-quadrupole time-of-flight/mass spectrometry (MS). HNA1, but not HNA2, increased IL-1β, IL-6, and TNF-α mRNA and protein expression in leukocytes from both healthy volunteers and patients with cirrhosis. Moreover, HNA1 up-regulated the expression of eicosanoid-generating enzymes (i.e., cyclooxygenase-2 [COX-2] and microsomal prostaglandin E [PGE] synthase 1) and the production of inflammatory eicosanoids (PGE2 , PGF2α , thromboxane B2 , and leukotriene B4 ), as determined by LC-electrospray ionization-MS/MS. The inflammatory response to HNA1 was more pronounced in peripheral blood mononuclear cells (PBMCs) and marginal in polymorphonuclear neutrophils. Kinome analysis of PBMCs revealed that HNA1 induced the phosphorylation of p38 mitogen-activated protein kinase, the inhibition of which blocked HNA1-induced cytokine and COX-2 induction. Conclusion: HNA1 triggers an inflammatory response in PBMCs, providing a rationale for its removal and replacement by reduced albumin in the prevention of systemic inflammation in patients with advanced liver disease.
Note: Versió postprint del document publicat a: https://doi.org/10.1002/hep.30135
It is part of: Hepatology, 2018, vol. 68, num. 5, p. 1937-1952
URI: http://hdl.handle.net/2445/130318
Related resource: https://doi.org/10.1002/hep.30135
ISSN: 0270-9139
Appears in Collections:Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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