Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Lab Chip. 2023 Dec 5;23(24):5180-5194. doi: 10.1039/d3lc00486d.
Interstitial fluid uptake and retention by lymphatic vessels (LVs) play a role in maintaining interstitial fluid homeostasis. While it is well-established that intraluminal lymphatic valves in the collecting LVs prevent fluid backflow (secondary lymphatic valves), a separate valve system in the initial LVs that only permits interstitial fluid influx into the LVs, preventing fluid leakage back to the interstitium (primary lymphatic valves), remains incompletely understood. Although lymphatic dysfunction is commonly observed in inflammation and autoimmune diseases, how the primary lymphatic valves are affected by acute and chronic inflammation has scarcely been explored and even less so using lymphatic models. Here, we developed a human initial lymphatic vessel chip where interstitial fluid pressure and luminal fluid pressure are controlled to examine primary lymph valve function. In normal conditions, lymphatic drainage (fluid uptake) and permeability (fluid leakage) in engineered LVs were maintained high and low, respectively, which was consistent with our understanding of healthy primary lymph valves. Next, we examined the effects of acute and chronic inflammation. Under the acute inflammation condition with a TNF-α treatment (2 hours), degradation of fibrillin and impeded lymphatic drainage were observed, which were reversed by treatment with anti-inflammatory dexamethasone. Surprisingly, the chronic inflammation condition (repeated TNF-α treatments during 48 hours) deposited fibrillin to compensate for the fibrillin loss, showing no change in lymphatic drainage. Instead, the chronic inflammation condition led to cell death and disruption of lymphatic endothelial cell-cell junctions, increasing lymphatic permeability and fluid leakage. Our human lymphatic model shows two distinct mechanisms by which primary lymphatic valve dysfunction occurs in acute and chronic inflammation.
淋巴管（LVs）摄取和保留间质液在维持间质液动态平衡中发挥作用。虽然收集 LVs 中的管腔内淋巴管瓣膜可防止液体反流（次级淋巴瓣膜）已得到充分证实，但最初 LVs 中还存在另一个瓣膜系统，仅允许间质液流入 LVs，防止液体漏回间质（初级淋巴瓣膜），但该系统尚未完全被理解。尽管淋巴管功能障碍在炎症和自身免疫性疾病中很常见，但急性和慢性炎症如何影响初级淋巴瓣膜尚未得到充分探索，甚至在使用淋巴管模型时也很少进行探索。在这里，我们开发了一种人初始淋巴管芯片，可以控制间质液压力和管腔液压力来检查初级淋巴瓣膜功能。在正常情况下，工程化 LVs 的淋巴引流（液体摄取）和通透性（液体渗漏）分别保持较高和较低，这与我们对健康初级淋巴瓣膜的理解一致。接下来，我们检查了急性和慢性炎症的影响。在 TNF-α 处理（2 小时）的急性炎症条件下，观察到纤维蛋白溶解和淋巴引流受阻，用抗炎药地塞米松治疗可逆转这种情况。令人惊讶的是，慢性炎症条件（48 小时内重复 TNF-α 处理）会沉积纤维蛋白溶解以补偿纤维蛋白溶解的损失，淋巴引流没有变化。相反，慢性炎症条件会导致细胞死亡和淋巴管内皮细胞-细胞连接中断，增加淋巴通透性和液体渗漏。我们的人淋巴管模型显示了初级淋巴瓣膜功能障碍在急性和慢性炎症中发生的两种截然不同的机制。
