Trovato Francesca Maria, Artru Florent, Sheth Roosey, Abdalla Rima, Wilson Joseph, Broderick Anna, Smith John, Atkinson Stephen, McPhail Mark J
School of Immunology and Microbial Sciences, King's College London, London, UK.
Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK.
J Clin Transl Hepatol. 2025 Aug 28;13(8):655-664. doi: 10.14218/JCTH.2025.00074. Epub 2025 Jun 24.
Liver failure syndromes are characterised 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, hypothesising 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.
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.
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, = 0.000216413) and ACLF (log fold change = 4.62, = 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) ( < 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%).
ADM is increased in liver failure, whereas AMBP1 is reduced. ADM affects monocyte function, increasing Mer Tyrosine Kinase and promoting a pro-restorative, anti-inflammatory phenotype.
肝衰竭综合征的特征是免疫反应失调导致免疫麻痹。肾上腺髓质素（ADM）是一种强效血管舒张剂和免疫调节剂。本研究旨在探讨ADM在肝衰竭中的作用，假设ADM与肾上腺髓质素结合蛋白（AMBP）1之间存在有害的失衡，这种失衡促进单核细胞/巨噬细胞向促修复表型和功能转变。
纳入2020年4月至2024年6月期间连续的急性肝衰竭（ALF）、慢加急性肝衰竭（ACLF）和失代偿期肝硬化患者以及健康对照（HC）。分离外周血单个核细胞/单核细胞并用于RNA测序和细胞培养。采用酶联免疫吸附测定法检测ADM和AMBP1。
纳入54例ALF患者、25例ACLF患者、9例失代偿期肝硬化患者和16例HC。与HC相比，ALF（对数倍变化 = 5.88，P = 0.000216413）和ACLF（对数倍变化 = 4.62，P = 0.00057122）患者分离的单核细胞中ADM表达增加。ALF患者血浆ADM浓度（1684±1156 pg/mL）高于ACLF患者（836.1±765.2 pg/mL）和HC（164.8±62.73 pg/mL）。与ACLF（126.3±72.23 μg/mL）和HC（252.8±159.7 μg/mL）相比，ALF患者的AMBP1显著降低（P < 0.0001，ALF与HC相比）。脂多糖处理可增加外周血单个核细胞上清液中的ADM浓度（ALF组n = 6；561.4±1038 pg/mL vs. 259.2±213.7 pg/mL，ACLF组n = 4；3202±491.2 vs. 1757±1689 pg/mL）。用脂多糖培养后，表达Mer酪氨酸激酶的CD14细胞百分比降低（2.077±0.87%）；然而，与100 nM ADM共培养可恢复该表型（3.852±1.063%）。
肝衰竭时ADM升高，而AMBP1降低。ADM影响单核细胞功能，增加Mer酪氨酸激酶并促进促修复、抗炎表型。
