Abstract
Background & AimsInfection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction.MethodsUsing samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production.ResultsWe show that hepatic production of PGE2 via the cyclo-oxygenase 1–microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)–DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor.ConclusionsPGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission.Lay summaryPatients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation.
Highlights
An estimated 2 million deaths worldwide are currently attributable to liver disease, a substantial increase from 676,000 (1.5%) in 1980 [1,2]
Journal Pre-proof Values were highest in hospitalised acute decompensation/acute-on-chronic liver failure (AD/Acute-on-Chronic-Liver Failure (ACLF)) patients, and patients with cirrhosis and ascites refractory to medical management attending the outpatients department for paracentesis (OPDs) demonstrated intermediate levels (Figure 1A, B)
The lower serum albumin concentrations in AD/ACLF patients compared to OPD (p
Summary
An estimated 2 million deaths worldwide are currently attributable to liver disease, a substantial increase from 676,000 (1.5%) in 1980 [1,2]. Journal Pre-proof overall US inpatient cirrhosis mortality rates fell from 2002-2010, actual mortality risk from infection or sepsis increased [4]. Monocyte dysfunction has been defined as reduced monocyte HLA-DR expression (Human Leukocyte Antigen–DR isotype) [10] and reduced ex-vivo endotoxin (LPS)-induced Tumour Necrosis Alpha (TNF) production [11,12,13,14,15], and is associated with increased infection rates [16,17,18]. Several studies detail circulating monocyte dysfunction in advanced liver disease [11,19] and persistently low expression of HLA-DR was associated with increased secondary infection and 28-day mortality [20]. Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. We previously demonstrated elevated prostaglandin (PG)E2 was a mediator of monocyte dysfunction in cirrhosis, and here examined PGE2 signalling in outpatients with ascites and hospitalised acute decompensation inpatients to identify potential therapeutic targets aimed at improving monocyte dysfunction
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