Executive Summary : | Chronic liver diseases (CLD) are a significant global health issue, causing significant morbidity and mortality. The gut-liver axis plays a crucial role in the pathogenesis and progression of CLD, with the gut lymphatic vascular system connecting the gut with the systemic circulation via the thoracic duct. These vessels maintain tissue homeostasis, remove microbial debris, and regulate immunity in the intestine. The mesenteric lymphatic vessels and nodes serve immune-regulatory functions, with lymphatic capillaries lined by lymphatic endothelial cells (LyECs).
The study hypothesizes that changes in mesenteric LyECs due to increased gut bacterial load cells significantly lead to changes in gut immunity, increasing systemic inflammation and precipitation of hepatic injury in cirrhosis, leading to acute decompensation of liver disease. The phenotype and functions of mesenteric LyECs in orchestrating immune responses towards gut-derived pathogens in liver cirrhosis are being investigated. A specific mutant of VEGF-C (Cys156Ser) is proposed as a LyEC-targeted therapy to facilitate gut lymphangiogenesis, improve pathogen clearance in the mesentery, strengthen local gut immunity, and attenuate systemic inflammation. The therapeutic potential of VEGF-C as a pro-lymphangiogenic factor has been reported in gut inflammatory disorders, but there are no studies focused on pro-lymphangiogenic factors as therapeutic molecules for attenuating systemic inflammation in cirrhosis.
The study aims to explore the role of recombinant VEGF-C (Cys156Ser) as a specific therapy to modulate LyECs and target systemic inflammation in cirrhosis to prevent acute decompensation and clinical deterioration in cirrhotic patients. |