Targeting the adrenomedullin pathway may be a potential therapy for liver failure

Background and aims

Liver failure syndromes are characterized by a dysregulated immune response leading to immune paralysis. Adrenomedullin (ADM) is a potent vasodilator and immunoregulator. This study aimed to explore the role of ADM in liver failure, hypothesizing that there is a detrimental imbalance between ADM and adrenomedullin binding protein (AMBP)1 that promotes a switch of monocytes/macrophages towards a pro-restorative phenotype and function.

Methods

Consecutive patients with acute liver failure (ALF), acute-on-chronic liver failure (ACLF), and decompensated cirrhosis, as well as healthy controls (HC) were included between April 2020 and June 2024. Peripheral blood mononuclear cells/monocytes were isolated and used for RNA sequencing and cell culture. ADM and AMBP1 were measured by enzyme-linked immunosorbent assay.

Results

Fifty-four patients with ALF, 25 with ACLF, 9 with decompensated cirrhosis, and 16 with HC were included. ADM expression in isolated monocytes was increased in ALF (log fold change = 5.88, p = 0.000216413) and ACLF (log fold change = 4.62, p = 0.00057122) compared to HC. Plasma ADM concentration was higher in ALF (1,684 ± 1,156 pg/mL) vs ACLF (836.1 ± 765.2 pg/mL) and HC (164.8 ± 62.73 pg/mL). AMBP1 was significantly reduced in ALF (59.27 ± 44 µg/mL) vs ACLF (126.3 ± 72.23 µg/mL) and HC (252.8 ± 159.7 µg/mL) (p < 0.0001, ALF vs HC). Treatment with LPS increased ADM concentration in peripheral blood mononuclear cell supernatant (ALF n = 6; 561.4 ± 1,038 pg/mL vs 259.2 ± 213.7 pg/mL, ACLF n = 4; 3,202 ± 491.2 vs 1,757 ± 1,689 pg/mL). The percentage of CD14⁺ cells expressing Mer tyrosine kinase was reduced after culture with LPS (2.077 ± 0.87%); however, co-culture with ADM 100 nM restored the phenotype (3.852 ± 1.063%).

Conclusions

ADM is increased in acute liver failure syndromes (ALF and ACLF), and AMBP1 is, on the contrary, reduced, mirroring the severity of the disease expressed by the SOFA score. ADM affects monocyte function, increasing MerTK after LPS stimulation and promoting a pro-restorative, anti-inflammatory phenotype. Further studies are needed to fully understand how to modulate this pathway as a possible therapeutic target and restore monocyte function.