Table 1.
Eicosanoids, specialized pro-resolving mediators (SPMs) and lysophospholipids and their known pathways involved in acute liver failure.
| Class | Major pathway | Mediator | Known receptors | Pathophysiological roles in acute liver failure | Refs |
|---|---|---|---|---|---|
| Eicosanoids | COX | PGE1 | EPs | TNFα-iNOS dependent hepatoprotective effects ↑vasodilatation with ↑vascular supply Benefit not confirmed in randomized trials |
(68–73) |
| PGE2 | EPs | ↓APAP-liver injury through ↓NFkB, ↓iNOS, ↑wnt with ↓apoptosis ↑proliferation ↓viral-induced liver injury by ↓procoagulant activity ↑I/R injury by ↑proinflammatory macrophage through PGE2-EP4 axis ↑hepatocyte proliferation after mesenchymal stem cell transfusion by ↓inflammasome activation and ↑macrophage M2 phenotype |
(78–83, 85) | ||
| PGI2 | IP PPARδ |
↑liver perfusion in patients ↑hepatic blood flow, ↓pro-inflammatory cytokines and ↑survival in experimental models |
(74–77) | ||
| 5-LOX | LTB4 | BLT1 and 2 PPARα |
↓LTB4 either by 5-LOX inhibitor or FLAP inhibitor was associated with ↓necro-inflammatory features with ↓TNFα ↓Kupfer cell activation/number and ↓MMP2 in LPS/GalN and CCL4 models. |
(86, 87) | |
| CysLTs | CysLTR1 and 2 | ↑LTC4 in LPS/GalN model ↓CysLTs by CysLTR1 inhibition led to ↓necro-inflammatory features with ↓ROS, ↓JNK1/2 and ERK1/2 activation |
(88, 89) | ||
| SPMs | 5-LOX | LXA4 | ALX | ↓LPS/GalN-induced liver injury in dose dependent manner with ↓NFkB ↓Kupfer cell activation ↓cell deaths pathways | (91) |
| 5-, 12-, 15-LOX | RvD1 | DRV1 | ↓TNFα, ↓MPO, ↑Glutathione, ↓ROS alleviating liver injury in a HO-1 dependent manner in CCL4 model | (92) | |
| RvD2 | DRV2 | ↓NETs, ↓liver injury, ↑survival in double hit rat model of major burn | (93) | ||
| Lysophospholipids | SM | Ceramide | * | Pivotal in hepatocyte cell death ↑ in ALF ↑TNFα-induced hepatocyte damages and ↑apoptosis in LPS-GalN model ↓SAM level, ↑caspase activation and ↑liver damage in TNFα-induced liver injury |
(94–96) |
| SK1 and 2 | S1P | S1P1 to 5 | ↑in I/R models, ↑NFkB and iNOS activation, ↑mitochondrial depolarization, ↑neutrophils infiltration ↑in RHDV, ↑TNFα, ↑NFkB, ↑TLR4 expression in the liver ↑in CCL4 and DMN models, selective inhibition of S1P2 ↑hepatocyte proliferation ↓apoptosis through AKT activation in in TNFα-induced hepatocyte injury |
(97–100) |
*Ceramide act mainly as a precursor and is metabolized by ceramide kinase and ceramidase into the highly active ceramide 1 phosphate and sphingosine without any binding on a specific target receptor.
5-LOX, 5 lipoxygenase; AD, acute decompensation; ALX, lipoxin receptor; APAP, acetaminophen; BLT1 and 2, leukotriene B4 receptors; CCL4, carbon tetrachloride; COX, cyclooxygenase; CysLTs, cysteinyl leukotrienes; CysLTR1 and 2, Cysteinyl leukotrienes receptors; DMN, dimethylnitrosamine; DRV1 and 2, resolvins receptors; EPs, prostaglandin E receptors; ERK, extracellular signal-regulated kinase; FLAP, 5-LOX activating protein; HO-1, hemo oxygenase-1; iNOS, inductible NOS; IP, prostacyclin receptor; I/R, ischemia reperfusion; JNK, janus kinase; LTB4, leukotriene B4; LPS/GalN, lipopolysaccharide/d-galactosamine; LXA4, lipoxin A4; MMP2, metalloproteinase 2; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; NFkB, nuclear factor-kappa B; PGE1, prostaglandin E1; PGE2, prostaglandin E2; PGI2, prostacyclin; PPARδ, peroxisome proliferator-activated receptor; RHDV, rabbit hemorrhagic disease virus; ROS, reactive oxygen species; RvD1, resolvin D1; RvD2, resolvin D2; S1P, sphingosine 1 phosphate; S1P1 to 5, S1P receptors; SAM, S-adenosyl-L-methionine; SM, sphingomyelinase; SK1 and 2, sphingokinases; TNFα, tumor necrosis factor α.
Eicosanoids are indicated in red, SPMs in green and lysophospholipids in blue.