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 c... More
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 (PGE ， PGF ， TXB and LTB )， 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.
