Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway

Maini, Alexander A.; Bécares, Natalia; China, Louise; Tittanegro, Thais; Patel, Amit; Maeyer, Roel P.H. De; Zakeri, Nekisa; Long, Tu Vinh; Ly, Lucy; Gilroy, Derek W.; O’Brien, Alastair

doi:10.1016/j.jhepr.2021.100332

Cited by 6 publications

(5 citation statements)

References 47 publications

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“…Unknown concentrations were determined via interpolation to a reference curve generated from a series of known PGE 2 concentration assays. Our previous study has shown that although EIA measurements of PGE 2 were as much as ×20 higher than liquid chromatography–tandem mass spectrometry, EIA reproducibly produced qualitative differences between sample groups consistent with data from liquid chromatography–tandem mass spectrometry analysis ( 16 ).…”

Section: Methodssupporting

confidence: 77%

Targeted Albumin Infusions Do Not Improve Systemic Inflammation or Cardiovascular Function in Decompensated Cirrhosis

China¹,

Bécares²,

Camilla³

et al. 2022

Clin Transl Gastroenterol

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INTRODUCTION:Albumin is recommended in decompensated cirrhosis, and studies have shown potential immunomodulatory effects. However, 2 large trials of repeated albumin infusions demonstrated contrasting results between outpatients and hospitalized patients. We investigated markers of systemic inflammation, immune function, albumin binding, and cardiovascular function using samples from Albumin To prevenT Infection in chronic liveR failurE (ATTIRE) taken at baseline, day 5, and day 10 of the trial to identify why targeted albumin infusions had no effect in hospitalized patients.METHODS:Plasma samples were analyzed from 143 patients (n = 71 targeted albumin; n = 72 standard care at baseline) for cytokines, cardiovascular markers, prostaglandin E2, the effect of plasma on macrophage function, and albumin radioligand binding and oxidation status. The sample size was based on our feasibility study, and samples were selected by a trial statistician stratified by the serum albumin level and the presence of infection at randomization and analyses performed blinded to the study arm. Data were linked to 3-month mortality and treatment groups compared.RESULTS:Increased baseline model for end-stage liver disease score, white cell count, calprotectin, CD163, tumor necrosis factor, renin, atrial natriuretic peptide, and syndecan-1 were associated with 3-month mortality. Despite infusing substantially differing volumes of albumin, there were no significant differences in inflammatory markers, albumin–prostaglandin E2 binding, or cardiovascular markers between treatment arms.DISCUSSION:Contrary to many preclinical studies, targeted intravenous albumin therapy in hospitalized decompensated cirrhosis had no effect across a broad range of systemic inflammation, albumin function, and cardiovascular mediators and biomarkers compared with standard care, consistent with the null clinical findings.

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Section: Methodssupporting

confidence: 77%

Targeted Albumin Infusions Do Not Improve Systemic Inflammation or Cardiovascular Function in Decompensated Cirrhosis

China¹,

Bécares²,

Camilla³

et al. 2022

Clin Transl Gastroenterol

Self Cite

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“…Albumin was also recently incorporated into the MELD 3.0 score [ 21 ] and our results suggest these changes may improve MELD-based prognosis of HCC progression compared to the MELD-Na. Beyond direct effects of albumin on HCC biology, the role of prostaglandin E2-mediated depletion of albumin stores in advancing CAID and its role in systemic immune suppression are becoming clearer [ 11 , 22 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoalbuminemia Is a Hepatocellular Carcinoma Independent Risk Factor for Tumor Progression in Low-Risk Bridge to Transplant Candidates

Nunez

Sandow

Patel

et al. 2022

Cancers

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Due to active hepatocellular carcinoma (HCC) surveillance, many patients are diagnosed with early-stage disease and are usually amendable to curative treatments. These patients lack poor prognostic factors associated with Milan Criteria and alpha fetoprotein (AFP) biomarker levels. There are currently limited strategies to assess prognosis in the patients who remain at risk of post-treatment HCC progression. In a cohort of liver transplant (LT) candidates with HCC, this study seeks to identify factors prior to liver-directed therapy (LDT) associated with time to progression (TTP). This is a retrospective analysis of prospectively collected data from LT candidates with recently diagnosed HCC and receiving LDT as a bridge to LT at three interventional oncology programs within a single system (n = 373). Demographics, clinical hepatology and serology, and factors related to HCC burden were extracted and analyzed for associations with TTP risk. Albumin level below the cohort median (3.4 g/dL) emerged as an independent risk factor for TTP controlling for AFP > 20 ng/mL as well as Milan, T-stage, and Barcelona Clinic Liver Cancer (BCLC) stage individually. In modality-specific subgroup survival analysis, albumin-based TTP stratification was restricted to patients receiving first cycle microwave ablation (p = 0.007). In n = 162 patients matching all low-risk criteria for Milan, T-stage, BCLC stage, and AFP, the effect of albumin <3.4 g/dL remained significant for TTP (p = 0.004) with 2-year TTP rates of 68% (<3.4 g/dL) compared to 95% (≥3.4 g/dL). In optimal bridge to LT candidates with small HCC and low AFP biomarker levels, albumin level at treatment baseline provides an HCC-independent positive prognostic factor for risk of HCC progression prior to LT.

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“…The authors secondly explored how the PGE2 pathway modulate monocyte dysfunction in patients with AD, who might benefit the most from intervention to prevent ACLF. They reported that PGE2 is produced by both hepatocytes and circulating monocytes mainly via the COX-/microsomal PGES-1 and COX-2 pathways respectively ( 114 ). In this study, through a specific antagonist approach, PGE2 was shown to mediate monocyte dysfunction mainly via its EP4 receptor (instead of EP2) ( 114 ).…”

Section: Eicosanoidsmentioning

confidence: 99%

“…They reported that PGE2 is produced by both hepatocytes and circulating monocytes mainly via the COX-/microsomal PGES-1 and COX-2 pathways respectively ( 114 ). In this study, through a specific antagonist approach, PGE2 was shown to mediate monocyte dysfunction mainly via its EP4 receptor (instead of EP2) ( 114 ). In HBV-related ACLF, an increase in circulating PGE2 was also observed.…”

Section: Eicosanoidsmentioning

confidence: 99%

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids

et al. 2022

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Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described.

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Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway

Cited by 6 publications

References 47 publications

Targeted Albumin Infusions Do Not Improve Systemic Inflammation or Cardiovascular Function in Decompensated Cirrhosis

Targeted Albumin Infusions Do Not Improve Systemic Inflammation or Cardiovascular Function in Decompensated Cirrhosis

Hypoalbuminemia Is a Hepatocellular Carcinoma Independent Risk Factor for Tumor Progression in Low-Risk Bridge to Transplant Candidates

Lipids in Liver Failure Syndromes: A Focus on Eicosanoids, Specialized Pro-Resolving Lipid Mediators and Lysophospholipids

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