PDF(Pubmed)
Abstract：
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 in vitro 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.
摘要：
淋巴管（LV）对间质液的吸收和保留在维持间质液稳态中起作用。虽然已经确定收集LV中的腔内淋巴瓣膜可以防止液体回流（次级淋巴瓣膜），初始LV中的单独阀系统，仅允许间质液流入LV，防止液体泄漏回间质（原发性淋巴瓣膜），仍然不完全理解。尽管淋巴功能障碍通常在炎症和自身免疫性疾病中观察到，初级淋巴瓣膜如何受到急性和慢性炎症的影响几乎没有被研究，甚至更少使用体外淋巴模型。这里,我们开发了一种人体初始淋巴管芯片，其中控制间质液压力和腔液压力以检查原发性淋巴瓣膜功能。在正常情况下,工程LV的淋巴引流（液体吸收）和渗透性（液体泄漏）保持高和低，分别,这与我们对健康的原发性淋巴瓣膜的理解是一致的。接下来,我们检查了急性和慢性炎症的影响。在急性炎症条件下，用TNF-α治疗（2小时），观察到纤丝蛋白降解和淋巴引流受阻，通过抗炎地塞米松治疗可以逆转。令人惊讶的是,慢性炎症状况（在48小时内重复TNF-α治疗）沉积原纤维蛋白以补偿原纤维蛋白损失，淋巴引流没有变化。相反，慢性炎症导致细胞死亡和淋巴管内皮细胞连接的破坏，增加淋巴通透性和液体渗漏。我们的人类淋巴模型显示了两种不同的机制，在急性和慢性炎症中发生原发性淋巴瓣功能障碍。
