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The lymphatic system: A new frontier in hepatology

Lymphatic vessels maintain tissue fluid homeostasis through reabsorption of interstitial fluid and transport of lipids and waste materials. They also direct trafficking of immune cells and coordinate immune responses. The most recognized clinical manifestations of lymphatic vessel disorders are lymphedema and ascites, where buildup of tissue fluids occurs because of impaired lymphatic drainage. Knowledge gained in the last decade has connected dysfunction of lymphatic vessels to various health problems, including cancer, obesity, cardiovascular diseases, and gastrointestinal disorders, such as inflammatory bowel disease. The liver is the largest lymph-producing organ and accounts for nearly half of the body’s lymphatic fluid. However, the study of the lymphatic vascular system in the liver is often overlooked. Its regulation has been poorly investigated at cellular and molecular levels. Limited knowledge about the molecular markers specific to hepatic lymphatics and a lack of established experimental models and techniques for studying the lymphatic vasculature in postnatal livers impair our understanding of this area. Recent advances in the study of lymphatic vessels in other organs/tissues are largely attributable to identification of specific markers and advanced imaging technologies using transgenic mice. Lymph in the liver originates from plasma components of blood flow filtered through fenestrae of liver sinusoidal endothelial cells. These plasma components (fluids and proteins) enter into the space of Disse, the hepatic version of the interstitial space, and form lymph. Drainage continues to small lymphatic vessels around the portal tract area, ultimately leaving the liver for the systemic lymphatic system. Anatomically, lymphatic vessels are categorized into lymphatic capillaries and collecting lymphatic vessels. These vessels consist of one layer of lymphatic endothelial cells with different degrees of basement membrane and pericytes depending on their subtypes. The morphological details of the lymphatic vasculature in the liver remain to be defined. Hydrostatic pressure is the major driving force for plasma components to move from sinusoids to the space of Disse. Therefore, hemodynamic changes in the sinusoids influence the amount of lymph production. For example, production of lymph increases in cirrhosis with portal hypertension as a result of an elevated pressure in the sinusoids. When production of lymph exceeds the capacity of the lymphatic system, ascites results. To what degree the lymphatic vasculature can compensate for the increased production of lymph, or whether there is decreased uptake in cirrhosis, is not well understood. Future translational research in this area may yield clinical benefits. Besides tissue fluid homeostasis, lymphatic vessels collect fats and waste materials. In recent years, lymphatic vessels in the skin have received significant attention because of the recognition that normal lymphatic vessel function is vital to keep healthy skin and prevent age-related skin problems. Dysfunction of lymphatic vessels causes accumulation of subcutaneous fats, resulting in “sagging” skin, typical of the aging process. Like the skin, hepatic fat accumulation contributes to the pathogenesis of many liver diseases. In nonalcoholic fatty liver disease, it is plausible to consider that maintenance of normal lymph production and lymphatic vessel function would have significant benefits for a healthy liver. Another important function of lymphatic vessels is trafficking of immune cells. Immune cells at inflamed sites migrate to lymphatic vessels and further to lymph nodes for discharge. In addition, they interact with lymphatic vessels and promote lymphangiogenesis. Lymphangiogenesis is the process of new lymphatic vessel formation from preexisting lymphatic vessels, similar to that of angiogenesis. This occurs in Abbreviation: VEGF, vascular endothelial growth factor.