Antagonizing epigenetically controlled PAF/PAF-R pathway improves liver function during experimental cirrhosis.

Area of Science:

• Hepatology
• Immunology
• Molecular Biology

Background:

• Platelet-activating factor (PAF) is a pro-inflammatory mediator primarily produced by macrophages.
• PAF plays a significant role in inflammatory responses within the liver.
• Dysregulation of PAF signaling is implicated in liver diseases like cirrhosis.

Purpose of the Study:

• To investigate the regulation of Platelet-activating factor receptor (PAF-R) gene expression in experimental cirrhosis.
• To determine if antagonizing the PAF-R ligand improves liver function and reduces inflammation in cirrhosis.

Main Methods:

• Utilized a carbon tetrachloride (CCl4)-induced cirrhosis mouse model and human cirrhotic patient samples.
• Administered PAF antagonist BN-52021 and a DNA methyltransferase (DNMT) inhibitor (Aza) to mice.
• Analyzed Ptafr expression, DNA methylation, cytokine profiles, and liver damage markers.

Main Results:

• PAF-R expression was elevated in hepatic macrophages of cirrhotic patients and mice.
• PAF antagonism with BN-52021 reduced liver damage, improved endothelial function, and modulated the Th17-Treg axis.
• Ptafr gene expression was regulated by DNA demethylation of its promoter in hepatic macrophages.

Conclusions:

• PAF antagonist BN-52021 effectively counteracts PAF-R overexpression and ameliorates liver injury in cirrhosis.
• PAF-R overexpression in hepatic macrophages is driven by promoter DNA demethylation.
• Targeting the PAF-R/PAF signaling pathway offers a potential therapeutic strategy for liver cirrhosis.