Matches in SemOpenAlex for { <https://semopenalex.org/work/W2968336474> ?p ?o ?g. }
Showing items 1 to 61 of
61
with 100 items per page.
- W2968336474 abstract "Liver cirrhosis is one of the greatest causes of mortality in the world in the 21st century. The prevalence of liver disease is predicted to continue to rise precipitously and liver disease accounts for between 2% and 3% of annual worldwide deaths. Bacterial infection is the major cause of mortality in liver cirrhosis and these patients are highly prone to nosocomial infection. Innate immune dysfunction is strongly implicated in this process. O’Brien et al (Nature Med, 2014) showed prostaglandin E2 (PGE2) was markedly increased in these patients. However, traditional approaches to reducing PGE2 (such as NSAIDs) are contraindicated due to renal and gastrointestinal side effects. This study aimed to investigate PGE2 downstream signalling pathways to identify a more specific druggable target to reverse immune dysfunction in acute-on-chronic liver failure (ACLF) and cirrhotic patients in general. ACLF patients (mean modified End-Stage Liver Disease (MELD) score 19) were compared to outpatients with resistant ascites admitted for elective paracentesis and drainage, ‘ambulant’, cirrhotic patients and healthy volunteers (HV). PGE2 levels in plasma were significantly increased between HV (163.9pg/ml) and ACLF (563.8pg/ml). I demonstrated increased microsomal Prostaglandin-E-Synthase-1 expression in cirrhotic liver parenchyma and increased phospholipase A2 expression and cyclooxygenase (COX)-2:COX-1 expression ratio in monocytes. ACLF and ambulant patients had increased circulating cytokines, including IL-6, IL-8, and TNF-a, as well as demonstrating a monocyte phenotype of immune fatigue, with low HLA-DR. Ex vivo lipopolysaccharide (LPS)-whole blood stimulation demonstrated monocyte deactivation with significantly lower levels of TNF-a and IL-6 in ACLF vs HV (2.178ng/109monocytes vs 6.649ng/109monocytes and 4.492ng/109monocytes vs 12.256ng/109monocytes respectively). This was further reduced by addition of exogenous PGE2 at inflammatory site concentrations. PGE2 acts through four membrane-bound G protein-coupled receptors with different activities, EP1-4. Blockade of the EP4 receptor completely reversed reduction in both TNF-a and IL-6. Similar changes were seen locally using an in vivo model of inflammation, including increased PGE2 concentrations at a local inflammatory site. In summary, ACLF patients have PGE2-mediated monocyte deactivation via the EP4 receptor. Blockade of this receptor restored innate immune function. EP4 blockade has been shown to have a safe renal profile and I suggest this is a valid target for future immune-restorative therapy in ACLF." @default.
- W2968336474 created "2019-08-22" @default.
- W2968336474 creator A5008516056 @default.
- W2968336474 date "2018-12-28" @default.
- W2968336474 modified "2023-09-24" @default.
- W2968336474 title "The Role of Prostaglandin E2 in Innate Immune Dysfunction in Cirrhotic Liver Disease" @default.
- W2968336474 hasPublicationYear "2018" @default.
- W2968336474 type Work @default.
- W2968336474 sameAs 2968336474 @default.
- W2968336474 citedByCount "0" @default.
- W2968336474 crossrefType "dissertation" @default.
- W2968336474 hasAuthorship W2968336474A5008516056 @default.
- W2968336474 hasConcept C126322002 @default.
- W2968336474 hasConcept C136449434 @default.
- W2968336474 hasConcept C203014093 @default.
- W2968336474 hasConcept C2777075537 @default.
- W2968336474 hasConcept C2777214474 @default.
- W2968336474 hasConcept C2777956040 @default.
- W2968336474 hasConcept C2779102576 @default.
- W2968336474 hasConcept C2780496750 @default.
- W2968336474 hasConcept C71924100 @default.
- W2968336474 hasConcept C8891405 @default.
- W2968336474 hasConcept C90924648 @default.
- W2968336474 hasConceptScore W2968336474C126322002 @default.
- W2968336474 hasConceptScore W2968336474C136449434 @default.
- W2968336474 hasConceptScore W2968336474C203014093 @default.
- W2968336474 hasConceptScore W2968336474C2777075537 @default.
- W2968336474 hasConceptScore W2968336474C2777214474 @default.
- W2968336474 hasConceptScore W2968336474C2777956040 @default.
- W2968336474 hasConceptScore W2968336474C2779102576 @default.
- W2968336474 hasConceptScore W2968336474C2780496750 @default.
- W2968336474 hasConceptScore W2968336474C71924100 @default.
- W2968336474 hasConceptScore W2968336474C8891405 @default.
- W2968336474 hasConceptScore W2968336474C90924648 @default.
- W2968336474 hasLocation W29683364741 @default.
- W2968336474 hasOpenAccess W2968336474 @default.
- W2968336474 hasPrimaryLocation W29683364741 @default.
- W2968336474 hasRelatedWork W191610553 @default.
- W2968336474 hasRelatedWork W1988903574 @default.
- W2968336474 hasRelatedWork W1990009615 @default.
- W2968336474 hasRelatedWork W1995485902 @default.
- W2968336474 hasRelatedWork W2035395021 @default.
- W2968336474 hasRelatedWork W2067915951 @default.
- W2968336474 hasRelatedWork W2071426857 @default.
- W2968336474 hasRelatedWork W2081361232 @default.
- W2968336474 hasRelatedWork W2159858475 @default.
- W2968336474 hasRelatedWork W2209056371 @default.
- W2968336474 hasRelatedWork W2309826094 @default.
- W2968336474 hasRelatedWork W2348845542 @default.
- W2968336474 hasRelatedWork W2527411952 @default.
- W2968336474 hasRelatedWork W2583115086 @default.
- W2968336474 hasRelatedWork W2924833400 @default.
- W2968336474 hasRelatedWork W2967970541 @default.
- W2968336474 hasRelatedWork W2998932876 @default.
- W2968336474 hasRelatedWork W3002174151 @default.
- W2968336474 hasRelatedWork W3191338970 @default.
- W2968336474 hasRelatedWork W3211820474 @default.
- W2968336474 isParatext "false" @default.
- W2968336474 isRetracted "false" @default.
- W2968336474 magId "2968336474" @default.
- W2968336474 workType "dissertation" @default.