Mechanisms of liver fibrosis: The role of lymphatics

Chronic inflammation due to various etiologies, such as virus infection and metabolic and immune disorders, results in liver fibrosis, often progressing to cirrhosis, carcinogenesis and portal hypertension.  The lymphatic vessels regulate local inflammatory responses by serving as the sites of activated immune cell egression and thus help to prevent or reduce inflammation, linking its potential role for liver fibrosis. Despite its apparent relevance in liver health and disease, the liver lymphatic vascular system remains poorly understood. I will discuss: 1) the current knowledge of hepatic lymphatic vessels in health and disease, 2) how lymphangiogenesis (new lymphatic vessel formation) is regulated, and 3) functional changes in hepatic lymphatic vessels during the development and progression of liver fibrosis, and 4) the therapeutic potential of lymphangiogenesis for liver fibrosis. Currently, the impact of lymphangiogenesis on liver fibrosis remains unknown. Vascular endothelial growth factor-C (VEGF-C) is known as the most potent lymphangiogenic factor. We hypothesize that an induction of lymphangiogenesis by VEGF-C overexpression will reduce inflammation and block progression of liver fibrosis. We found that the number of lymphatic vessels significantly increases in fibrotic livers from cirrhotic patients and mouse models of liver fibrosis. Liver-specific delivery of VEGF-C via adeno-associated virus (AAV) further increases lymphangiogenesis in fibrotic livers, reduces liver inflammation and subsequent fibrosis. We speculate that while lymphangiogenesis actively takes place during the liver fibrogenesis, chronic inflammation eventually exceeds the protective capacity of lymphatic vessels, leading to the progression of liver fibrosis. In addition, it is possible that chronic inflammation may change phenotype of lymphatic endothelial cells and reduce their ability to regulate local inflammatory responses. However, VEGF-C-driven hepatic lymphangiogenesis reduces inflammation and blocks liver fibrosis, suggesting its therapeutic potential for the treatment of liver fibrosis.