Lymphatics in the liver

摘要 淋巴系统维持组织液平衡，调节局部炎症 反应。1，2肝脏淋巴系统仍知之甚少。这项拟议研究的目标是 加深对肝淋巴管生成机制(新淋巴管的形成)的认识 血管)和淋巴管在肝脏病理生理学中的作用。 血管内皮生长因子C(VEGF-C)是淋巴管生成的主要诱导物。我们的 初步研究表明，血管内皮生长因子C过表达可促进肝淋巴管生成 减少肝纤维化，提示治疗潜力。更多数据显示，肝脏的雪旺氏细胞 交感神经作为血管内皮生长因子-C的来源和募集者在肝淋巴管生成中起中心作用 巨噬细胞，它可能通过产生纤维连接蛋白-1(FN1)而促进肝淋巴管生成，a VEGFR3信号转导所必需的整合素底物。因此，我们假设 淋巴消融应该增加炎症和促进疾病的进展，并促进淋巴管的生成 在雪旺细胞和巨噬细胞通过血管内皮生长因子-C信号的驱动下，应该减轻炎症和抑制 疾病的发展。为了检验这些假设，我们提出了以下具体目标： 1.确定雪旺细胞驱动促进肝淋巴管生成的机制。 2.确定Kupffer细胞/巨噬细胞驱动的促进肝淋巴管生成的机制。 3.确定淋巴管生成在肝纤维化发生发展中的作用。 拟议的研究将从视觉和机械上阐明淋巴管的调节。 以及它们在肝纤维化/肝硬变中的功能重要性。此外，血管内皮生长因子-C过度表达和 随后诱导淋巴管生成以预防和治疗肝纤维化/肝硬变 门静脉高压症和腹水将被评估。此外，这项研究将大大有助于 通过探索相对不足的肝淋巴管区域来研究肝脏的进展 系统和神经系统。

SUMMARY The lymphatic system maintains tissue fluid homeostasis and regulates local inflammatory responses.1,2 The liver lymphatic system remains poorly understood. The goal of this proposed research is to advance our understanding of the mechanisms of hepatic lymphangiogenesis (the formation of new lymphatic vessels) and the role of lymphatic vessels in liver pathophysiology. Vascular endothelial growth factor C (VEGF-C) is the major inducer of lymphangiogenesis. Our preliminary studies have shown that enhanced hepatic lymphangiogenesis by VEGF-C overexpression reduces liver fibrosis, suggesting a therapeutic potential. Additional data show that Schwann cells of hepatic sympathetic nerves play a central role in hepatic lymphangiogenesis as a source of VEGF-C and as a recruiter of macrophages, which may contribute to hepatic lymphangiogenesis by producing fibronectin-1 (FN1), a substrate for integrins essential for VEGF-C/VEGF receptor 3 (VEGFR3) signaling. We thus hypothesize that lymphatic ablation should increase inflammation and promote disease progression, and lymphangiogenesis driven by Schwann cells and macrophages through VEGF-C signaling should alleviate inflammation and inhibit disease progression. To test these hypotheses, we propose the following Specific Aims: 1. Determine the Schwann cell-driven mechanisms that promote hepatic lymphangiogenesis. 2. Determine Kupffer cells/macrophages-driven mechanisms that promote hepatic lymphangiogenesis. 3. Determine the role of lymphangiogenesis in the development of liver fibrosis. The proposed research will elucidate the regulation of lymphatic vessels visually and mechanistically and their functional importance in liver fibrosis/cirrhosis. Further, the potential of VEGF-C overexpression and subsequent induction of lymphangiogenesis for the prevention and treatment of liver fibrosis/cirrhosis as well as portal hypertension and ascites will be evaluated. Furthermore, this research will significantly contribute to the advancement of the study of the liver by exploring relatively underexamined areas of the hepatic lymphatic system and nervous system.