Albuminomics

Oxidized Albumin Triggers a Cytokine Storm in Leukocytes Through P38 Mitogen-Activated Protein Kinase: Role in Systemic Inflammation in Decompensated Cirrhosis

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Oxidized Albumin Triggers a Cytokine Storm in Leukocytes Through P38 Mitogen-Activated Protein Kinase: Role in Systemic Inflammation in Decompensated Cirrhosis

Bibliographic info

  • Authors: 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
  • Journal: Hepatology, 2018, vol. 68, no. 5, pp. 1937–1952; DOI: 10.1002/hep.29992
  • Institutions: Hospital Clínic-IDIBAPS-CIBERehd, Barcelona, Spain; Medical University of Graz, Austria; EF Clif Consortium

Key question

Can oxidized albumin (HNA1, HNA2) directly trigger systemic inflammation by activating peripheral leukocytes through p38 MAPK, and does this explain the systemic inflammatory phenotype of decompensated cirrhosis?

Methods

  • Sample type: Human plasma; isolated peripheral blood leukocytes
  • Cohort: 48 healthy volunteers; 31 compensated cirrhosis (CC); 153 decompensated cirrhosis (DC); 72 DC + ACLF — CANONIC study (EF Clif Consortium); 29 European hospital centers
  • Albumin fractionation: Albumin separated into HMA, HNA1, and HNA2 fractions by IEC
  • Assays:
    • HNA1/HNA2 plasma levels by IEC-HPLC
    • Leukocyte incubation with purified albumin fractions → cytokine production (IL-1β, IL-6, IL-8, TNF-α) measured by ELISA
    • p38 MAPK phosphorylation: Western blot (p-p38 vs total p38)
    • ROS/RNS measurement: OxiSelect fluorescence assay
    • Antioxidant capacity assay
    • Arachidonic acid metabolite profiling (LTB4, PGE2, 15-HETE) by LC-ESI-MS/MS
    • Endotoxin assay (LAL)

Main findings

  1. HNA1 and HNA2 progressively elevated: CC < DC < ACLF; both fractions increase with disease severity (n=256 total cirrhosis patients)
  2. Oxidized albumin (HNA1 especially) triggers cytokine production in healthy leukocytes incubated with HNA1/HNA2 fractions → IL-1β, IL-6, IL-8, TNF-α all elevated vs HMA or commercial albumin
  3. p38 MAPK phosphorylation is the key intracellular signal activated by oxidized albumin in leukocytes
  4. ROS/RNS higher in HNA1/HNA2 fractions than HMA → oxidized albumin carries its own oxidative load
  5. Antioxidant capacity lower in HNA1/HNA2 fractions → loss of albumin’s scavenging role
  6. Arachidonic acid metabolites: oxidized albumin promotes LTB4 and PGE2 production by leukocytes — pro-inflammatory lipid mediator cascade
  7. Endotoxin excluded: all albumin fractions endotoxin-free → the pro-inflammatory effect is albumin-intrinsic, not LPS contamination

Mechanistic model

Cirrhosis → oxidative stress → Cys34 oxidation → HNA1 (reversible)/HNA2 (irreversible)
↓
Circulating oxidized albumin activates leukocytes via p38 MAPK
↓
Cytokine storm (TNF-α, IL-6, IL-1β, IL-8) + LTB4/PGE2 production
↓
Systemic inflammation → accelerates decompensation → ACLF → multi-organ failure

Clinical context

  • Disease: Liver fibrosis / cirrhosis systemic inflammation; DILI (oxidative stress mechanism)
  • CANONIC study (multi-center European; 2011 enrollment): provides the largest oxidized albumin dataset in cirrhosis to date
  • Implication: Oxidized albumin is not merely a passive biomarker — it is an active driver of systemic inflammation in cirrhosis. This has therapeutic implications: reducing oxidized albumin (e.g., through albumin infusion with functional albumin) may reduce inflammatory burden

Connections

  • HSA — oxidized forms as immunological danger signals
  • Oxidation — HNA1 (reversible) and HNA2 (irreversible) as active immune modulators
  • oettl-2013 — complementary finding; HNA2 predicts survival; here mechanism explained
  • das-2017-sah — hyperoxidized albumin also modulates neutrophils in severe AH (parallel mechanism)
  • fernandez-2019 — albumin therapy counteracts inflammation; mechanism via oxidized albumin neutralization
  • china-2018 — albumin counters lipid mediator-driven immune suppression; PGE2 link
  • domenicali-2014 — provides the isoform structural context for what HNA1/HNA2 mean

My take home notes

  • This paper provides the mechanistic link between albumin structural damage and systemic inflammation — the “why” behind why oxidized albumin levels matter clinically beyond just predicting survival.
  • p38 MAPK pathway is the intracellular mechanism: oxidized albumin acts like a DAMP (damage-associated molecular pattern) triggering innate immune activation.
  • The CANONIC study population (n=256 cirrhosis) provides excellent statistical power — this is not a small discovery study.
  • The LTB4/PGE2 link connects to china-2018 (PGE2-mediated immune suppression in AD/ACLF) — the same pro-inflammatory lipid mediators are produced by leukocytes in response to oxidized albumin.
  • For the SEB test context: the fact that oxidized albumin actively triggers inflammation implies that detecting early albumin oxidation (as the SEB test does) is not just a biomarker finding but may have direct mechanistic relevance.

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