Abstract
Portal hypertension (PH) is a major cause of morbidity and mortality in chronic liver disease. Infection and inflammation play a role in potentiating PH and pro-inflammatory cytokines, including TNF, are associated with severity of PH. In this study, cirrhotic bile duct ligated (BDL) rats with PH were treated with Infliximab (IFX, a monoclonal antibody against TNF) and its impact on modulation of vascular tone was assessed. BDL rats had increased TNF and NFkB compared to sham operated rats, and their reduction by IFX was associated with a reduction in portal pressure. IFX treatment also reduced hepatic oxidative stress, and biochemical markers of hepatic inflammation and injury. IFX treatment was associated with an improvement in eNOS activity and increased l-arginine/ADMA ratio and DDAH1 expression. In vitro analysis of HepG2 hepatocytes showed that DDAH1 protein expression is reduced by oxidative stress, and this is in part mediated by post-transcriptional regulation by the 3′UTR. This study supports a role for the DDAH1/ADMA axis on the effect of inflammation and oxidative stress in PH and provides insight for new therapies.
Highlights
Bacterial translocation, measured by its surrogate marker serum bacterial DNA, is correlated with both systemic inflammation and PH3
This is despite normal, or even increased, levels of hepatic endothelial NOS isoform (eNOS) protein expression in cirrhosis[26,27,28]. This apparent paradox suggests that post-translational modification or the presence of eNOS inhibitors may be the cause of reduced eNOS activity
DDAH1 protein is further reduced in cells treated with 100 uM H2O2
Summary
Bacterial translocation, measured by its surrogate marker serum bacterial DNA, is correlated with both systemic inflammation and PH3. Decreased eNOS activity has been implicated in the pathobiology of portal hypertension This is despite normal, or even increased, levels of hepatic eNOS protein expression in cirrhosis[26,27,28]. This apparent paradox suggests that post-translational modification or the presence of eNOS inhibitors may be the cause of reduced eNOS activity. DDAH1 activity is sensitive to oxidative stress[36,37,38] This suggests a potential role for the impact of oxidative stress on the DDAH1-ADMA axis and resulting changes in intrahepatic vascular tone in cirrhosis patients
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