Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.

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 e...

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Autores: 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
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2018
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/130318
Acceso en línea:https://hdl.handle.net/2445/130318
Access Level:acceso abierto
Palabra clave:Cirrosi hepàtica
Inflamació
Leucòcits
Hepatic cirrhosis
Inflammation
Leucocytes
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spelling Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.Alcaraz-Quiles, JoséCasulleras, MireiaOettl, KarlTitos Rodríguez, EstherFlores Costa, RogerDuran Güell, MartaLópez Vicario, CristinaPavesi, MarcoStauber, Rudolf E.Arroyo, VicenteClària i Enrich, JoanCirrosi hepàticaInflamacióLeucòcitsHepatic cirrhosisInflammationLeucocytesDecompensated 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.Wiley2018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/130318Articles publicats en revistes (Biomedicina)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: https://doi.org/10.1002/hep.30135Hepatology, 2018, vol. 68, num. 5, p. 1937-1952https://doi.org/10.1002/hep.30135(c) American Association for the Study of Liver Diseases, 2018info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1303182026-05-27T06:46:51Z
dc.title.none.fl_str_mv Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
title Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
spellingShingle Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
Alcaraz-Quiles, José
Cirrosi hepàtica
Inflamació
Leucòcits
Hepatic cirrhosis
Inflammation
Leucocytes
title_short Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
title_full Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
title_fullStr Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
title_full_unstemmed Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
title_sort Oxidized albumin triggers a cytokine storm in leukocytes through p38 MAP kinase: role in systemic inflammation in decompensated cirrhosis.
dc.creator.none.fl_str_mv 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
author Alcaraz-Quiles, José
author_facet 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
author_role author
author2 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
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cirrosi hepàtica
Inflamació
Leucòcits
Hepatic cirrhosis
Inflammation
Leucocytes
topic Cirrosi hepàtica
Inflamació
Leucòcits
Hepatic cirrhosis
Inflammation
Leucocytes
description 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.
publishDate 2018
dc.date.none.fl_str_mv 2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/130318
url https://hdl.handle.net/2445/130318
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: https://doi.org/10.1002/hep.30135
Hepatology, 2018, vol. 68, num. 5, p. 1937-1952
https://doi.org/10.1002/hep.30135
dc.rights.none.fl_str_mv (c) American Association for the Study of Liver Diseases, 2018
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) American Association for the Study of Liver Diseases, 2018
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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