Table 2.
Eicosanoids, specialized pro-resolving mediators (SPMs) and lysophospholipids and their known pathways involved in acute on chronic liver failure.
| Class | Major pathway | Mediator | Known receptors | Pathophysiological roles in acute on chronic liver failure | Refs |
|---|---|---|---|---|---|
| Eicosanoids | COX | PGE2 | EPs | ↑by oxidized albumin form. ↑in experimental models of ACLF. ↓proinflammatory macrophages phenotype with ↓bacterial killing modulated by albumin infusion in a EP2 and/or 4 dependent manners. ↑proinflammatory monocytes and neutrophils and ↓phagocytosis in HBV-ACLF model. |
(111–115) |
| TXAS | 12-HHT | BLT2 | ↑in ACLF and part of the minimal fingerprint differentiating ACLF vs. patients with AD ↑ with kidney, coagulation, and circulatory failure |
(101) | |
| 5-LOX | LTE4 | CysLTRs | ↑in ACLF and part of the minimal fingerprint differentiating ACLF vs. patients with AD ↑with disease severity, bacterial infection, portal hypertension and mortality. |
(101) | |
| CYP4A/F | 20-HETE | GPR75 | ↑with hepatic steatosis, neutrophils infiltration and mortality in AH. Inversely correlated to albumin concentration. |
(35, 102) | |
| SPMs | 5-LOX | LXA5 | TP ()? | ↓in ACLF, negatively correlates with IL-8 level, cell death marker, liver failure and death. | (101, 116) |
| 5-, 15-LOX | RvD1 | DRV1 ALX |
↓excessive inflammation ↓neutrophils recruitment ↓bacterial burden ↑phagocytosis monocytes and macrophages in CLP sepsis models. ↓HMGB1 ↓excessive inflammation ↓neutrophils recruitment in LPS/GalN model ↓hepatocyte apoptosis in a dose dependent manner in LPS/GalN model |
(117, 118) | |
| CYP450, aa-COX, 5-LOX | RvE1 | ERV | ↑mitochondrial function ↓LPS induced cardiac dysfunction ↓bacterial burden in sepsis models ↑phagocytosis of macrophages | (119, 120) | |
| 12-LOX | MCTR1 | CysLTRs antagonist | ↓LPS induced kidney and cardiac dysfunction ↓ferroptosis and ↑survival in CLP sepsis model | (121–123) | |
| aa-COX, 5-LOX | AT-RvD1 | ALX | ↓integrin expression in kidney ↓IL-6 level and blocked STAT3 phosphorylation ↓kidney injury in LPS induced AKI | ||
| Lysophospholipids | SK1 and 2 | S1P | S1P1 to 5 | ↓observed in patients with AD, ALCF and sepsis ↓associated with worse outcome ↑pathogen recognition and killing modulated by albumin level |
(124–128) |
| PLA1 and 2 | LPC | TLR 2/4 GPR132 |
↓ in ACLF and correlated to ACLF grade and anti-inflammatory monocyte phenotype ↑after albumin infusion ↑neutrophils bactericidal activity and ↓mortality in CLP sepsis model |
(124, 129–131) | |
| ATX | LPA | LPAR1 to 6 | ↑in ACLF ↓pro-regulatory phenotype of CD14+ monocytes: ↑TNFα and IL-6 secretion but no effects on phagocytosis |
(129) |
5-LOX, 5 lipoxygenase; aa-COX, aspirin acetylated cyclooxygenase; AD, acute decompensation; AH, alcoholic hepatitis; AKI, acute kidney injury; ALX, lipoxin receptor; ATX, autotaxin; BLT 2, leukotriene B4 receptor 2; CLP, caecum ligation an puncture; COX, cyclooxygenase; CysLTRs, cysteinyl leukotrienes receptors; DRV, resolvins receptor 1; EPs, prostaglandin E receptors; ERV, resolvin receptor; GPR75, G-protein coupled receptor 75; HMGB1, high mobility group box-1; LPA, lysophosphatidic acid; LPAR1 to 6, lysophosphatidic acid receptors; LPC, lysophosphatidylcholine; LPS/GalN, lipopolysaccharide/d-galactosamine; LTE4 leukotriene E4; LXA5, lipoxin A5; MCTR1, maresin conjugates in tissue regeneration 1; MPO, myeloperoxidase; PGE1, prostaglandin E1; PGE2, prostaglandin E2; PLA1 and 2, phospholipase A1 and A2; RvD1, resolvin D1; RvE1, resolvin E1; S1P, sphingosine 1 phosphate; S1P1 to 5, S1P receptors; SK1 and 2, sphingokinases; STAT3, Signal transducer and activator of transcription 3; TNFα, tumor necrosis factor α, TP, thromboxane receptor; TXAS, thromboxane synthase.
Eicosanoids are indicated in red, SPMs in green and lysophospholipids in blue. Lipid mediator underlined means that the pathophysiological roles have been reported in sepsis models only.