Background and Aims: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 th...Background and Aims: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.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±44μg/mL)vs.ACLF(126.3±72.23μg/mL)and HC(252.8±159.7μg/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 liver failure,whereas AMBP1 is reduced.ADM affects monocyte function,increasing Mer Tyrosine Kinase and promoting a pro-restorative,anti-inflammatory phenotype.展开更多
基金supported by the MRC IAA 2021 King’s College London(MR/X502923/1).
文摘Background and Aims: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.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±44μg/mL)vs.ACLF(126.3±72.23μg/mL)and HC(252.8±159.7μg/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 liver failure,whereas AMBP1 is reduced.ADM affects monocyte function,increasing Mer Tyrosine Kinase and promoting a pro-restorative,anti-inflammatory phenotype.
