Thématique :
- Foie
Originalité :
Très original
Solidité :
A confirmer
Doit faire évoluer notre pratique :
Pas encore
Nom du veilleur :
Professeur Christine SILVAIN
Coup de coeur :
  2018 Nov;68(5):1937-1952.  
  doi: 10.1002/hep.30135.  
  Oxidized Albumin Triggers a Cytokine Storm in Leukocytes Through P38 Mitogen-Activated Protein Kinase: Role in Systemic Inflammation in Decompensated Cirrhosis.  
  Alcaraz-Quiles J, Casulleras M, Oettl K, Titos E, Flores-Costa R, Duran-Güell M, López-Vicario C, Pavesi M, Stauber RE, Arroyo V, Clària J  


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 , PGF , 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.

Question posée
Etudier la capacité de formes oxydées d’albumine (nonmercaptalbumine humaine 1 (HNA1) and HNA2, biomarqueurs du stress oxydant dans la cirrhose) d’entraîner une inflammation systémique activant les leucocytes périphériques.
Question posée
Des taux plasmatiques plus élevés d’HNA1 et d’HNA2 sont mis en évidence chez les patients in patients avec cirrhoses comparés aux volontaires sains et augmentent progressivement de la cirrhose compensée à décompensée et vers ACLF. HNA1 seulement augmente les ARNm et l’expression protéique d’ IL-1β, IL-6, and TNF-α des leucocytes des volontaires sains et des cirrhotiques et augmente l’expression des cyclooxygénase-2 [COX-2] et des prostaglandines E [PGE] synthase microsomale1) in vitro.

Une piste originale pour réduire l’inflammation systémique au cours de la cirrhose : utilisation d’albumine « réduite débarrassée » d’HNA1 ou inhibiteur sélectif comme le selonsertib si l’activation d’HNA1 passe par l’activation d’ASK1.