Hepatic lymphatics in alcohol-associated liver disease

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SUMMARY A subset of patients with alcohol-associated liver disease (ALD) develop severe alcoholic hepatitis (AH), carrying a very poor prognosis. Control of inflammation is a key to the treatment of AH. Hepatic lymphatics are highly involved in the regulation of the inflammatory response by discharging extravasated fluids, inflammatory mediators, antigens, and antigen-presenting cells to lymph nodes outside the liver. However, how the hepatic lymphatic system is involved in the development of ALD remains largely unknown. The goal of this exploratory study is to advance our understanding of hepatic lymphatics in the progression of AH and explore whether increasing lymphatic vessels (LVs) and lymphatic drainage can be a novel therapeutic strategy for AH. Given that lymphatics generally help to reduce tissue inflammation, we hypothesize that chronic alcohol consumption may impair hepatic lymphatic endothelial cell (EC) function and lymphatic drainage, facilitating the progression to AH. Contrarily, enhancing lymphangiogenesis (new LV formation) via overexpression of vascular endothelial growth factor (VEGF)-C, the most potent lymphangiogenic factor, may ameliorate AH. To test these hypotheses, we propose the following two Aims: Aim 1. Determine the role of the hepatic lymphatic system in AH. Aim 2. Explore the potential of the VEGF-C mRNA LNP (lipid nanoparticle) technology for the treatment of severe AH. This study will explore an important, but poorly understood subject, liver lymphatics in ALD, addressing the effect of alcohol on hepatic lymphatic functions and its implications in the development of AH. Results from the two Aims above will provide the foundation for many future studies to advance our understanding of the lymphatic system in liver disease in general and AH in particular, including a study addressing the molecular mechanism of lymphatic impairment by alcohol as well as a study aiming at clinical use of VEGF-C mRNA-LNP for the treatment of AH.