Abstract
Genetic variants and dysfunctional monocyte had been reported to be associated with infection susceptibility in advanced cirrhotic patients. This study aims to explore genetic predictive markers and relevant immune dysfunction that contributed to severe sepsis in febrile acute de-compensated cirrhotic patents. Polymorphism analysis of candidate genes was undergone in 108 febrile acute de-compensated cirrhotic patients and 121 healthy volunteers. Various plasma inflammatory/regulatory cytokines, proportion of classical (CD 16-, phagocytic) and non-classical (CD16+, inflammatory) monocytes, lipopolysaccharide (LPS)-stimulated toll-like receptor 4 (TLR4) and intracellular/extracellular cytokines on cultured non-classical monocytes, mCD14/HLA-DR expression and phagocytosis of classical monocytes were measured. For TLR4+896A/G variant allele carriers with severe sepsis, high plasma endotoxin/IL-10 inhibits HLA-DR expression and impaired phagocytosis were noted in their classical monocyte. In the same group, increased non-classical monocyte subset, enhanced LPS-stimulated TLR4 expression and TNFα/nitrite production, and systemic inflammation [high plasma soluble CD14 (sCD14) and total nitric oxide (NOx) levels] were noted. For CD14-159C/T variant allele carriers with severe sepsis, persist endotoxemia inhibited mCD14/HLA-DR expression and impaired phagocytosis of their classical monocyte. In the same group, increased non-classical monocyte subset up-regulated TLR4-NFκB-iNOS and p38MAPK pathway, stimulated TNFα/nitrite production and elicited systemic inflammation. In febrile acute de-compensated cirrhotic patients, TLR4+896A/G and CD14-159C/T polymorphisms-related non-classical and classical monocytes dysfunction resulted in increased severe sepsis risk. Malnutrition, high plasma endotoxin and sCD14 levels, single TLR4+896A/G or CD14-159C/T variant allele carriers and double variant allele carriers are significant predictive factors for the development of severe sepsis among them.
Highlights
Acute de-compensated cirrhotic patients are suffered from compromise hepatic immune surveillance, impaired phagocytosis and high severe sepsis-related mortality [1]
The enrolled afebrile compensated cirrhotic patients were characterized by lower Child-Pugh class, lower model for end stage liver disease (MELD) score, relative normal serum sodium concentration, higher serum albumin, lower serum bilirubin and less prothrombin time prolongation than febrile de-compensated cirrhotic patients (S2 Table)
Cases complicated with severe sepsis had significantly higher plasma soluble CD14 (sCD14), IL-10, nitric oxide (NOx) levels, higher proportion of moderate/ massive ascites, lower serum albumin and more episodes of overall previous infection per patients than those non-severe sepsis cases (S2 Table and S1F Fig)
Summary
Acute de-compensated cirrhotic patients are suffered from compromise hepatic immune surveillance, impaired phagocytosis and high severe sepsis-related mortality [1]. Poor response to bacterial challenge, increased susceptibility to bacterial infection, high severe sepsis-related mortality had been reported in advanced cirrhotic patients [2,3]. In response to bacterial invasion, Toll-like receptor-4(TLR4)/MD-2 complex and its coreceptor membrane-bound CD14 (mCD14) on leukocyte recognizes lipopolysaccharide (LPS) to activate NFκB-mediated pro-inflammatory signaling and phagocytosis [4,5,6,7]. An association between TLR4 genetic polymorphism and infection susceptibility has been reported in patients with and without cirrhosis [8,9,10]. It had been reported that CD14-159C/T polymorphism can affect mCD14 expression, plasma sCD14 levels, increased septic shock susceptibility [11,12,13,14]
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