Assistant Professor Cornell University Ithaca, New York, United States
Introduction: 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.
Materials and
Methods: 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.
Results, Conclusions, and Discussions: Our study provides some of the first examinations of primary lymphatic valve function using an in vitro microfluidic chip model, demonstrating impaired lymphatic drainage and permeability under inflammation due to the degradation of anchoring filaments and related lymphatic junction disruption. Regarding the relative contributions of acute or chronic inflammation to the primary lymph valve dysfunction, acute inflammation mainly impaired lymphatic drainage, but chronic inflammation impaired permeability, potentially exacerbating the dysfunction. This primary lymph valve chip may provide a unique platform for furthering our understanding and rendering feasible high-throughput testing of drug candidates in the lymphatic microenvironment.
