Hepatic lymphatics in alcohol-associated liver disease

总结 酒精相关性肝病（ALD）患者的一个子集发展为重度酒精性肝炎 (AH)预后很差。控制炎症是治疗AH的关键。肝 抗炎药高度参与炎症反应的调节， 液体、炎症介质、抗原和抗原呈递细胞转移到肝外的淋巴结。 然而，肝淋巴系统如何参与ALD的发展仍然是未知的。 这项探索性研究的目的是提高我们对肝硬化进展中肝硬化的认识。 AH并探讨增加淋巴管（LV）和淋巴引流是否可以成为一种新的治疗方法 战略为。 考虑到抗炎药通常有助于减少组织炎症，我们假设慢性炎症是由炎症引起的。 饮酒可能损害肝淋巴管内皮细胞（EC）功能和淋巴引流， 促进向AH的发展。间接地，增强淋巴管生成（新的LV形成），通过 血管内皮生长因子（VEGF）-C是最有效的淋巴管生成因子， 改善AH。为了验证这些假设，我们提出以下两个目标： 目标1.确定肝淋巴系统在AH中的作用。 目标2.探索VEGF-C mRNA LNP（脂质纳米粒）技术治疗 严重啊。 这项研究将探讨一个重要的，但了解不多的主题，ALD的肝脏代谢，解决 酒精对肝淋巴功能的影响及其在AH发生中的意义。结果 上述两个目标将为未来的许多研究提供基础，以促进我们对 淋巴系统在肝脏疾病中的作用，特别是AH，包括一项研究， 酒精引起的淋巴损伤机制以及针对VEGF-C mRNA-LNP临床应用的研究 治疗AH。

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.