Chou Chou, Paredes Camila Ceballos, Summers Barbara, Palmer-Johnson Jade, Trivedi Anjali, Bhagwani Aneel, Hansen Kasper B, Kristensen Anders S, Gyoneva Stefka, Swanger Sharon A, Traynelis Stephen F, Reed Hasina Outtz
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA.
Nat Cardiovasc Res. 2025 Jul 17. doi: 10.1038/s44161-025-00681-7.
The lung lymphatic vasculature is capable of remarkable increases in lymphatic drainage in settings of inflammation and edema; however, the mechanisms driving this are not clear. Here we show that lung injury transforms the configuration of lung lymphatic endothelial cell junctions from a continuous 'zippered' configuration to a discontinuous and permeable 'button' configuration. Despite similarity to the junctional changes often seen in leaky and dysfunctional blood vessels, we find that the shift to button junctions in the lymphatic vasculature has an opposite effect, resulting in augmented lung lymphatic drainage. Mechanistically, we demonstrate that lung lymphatic button junction formation in models of lung injury is dependent on the thrombin receptor protease-activated receptor 1, a known mediator of blood vessel permeability. These results uncover a previously unknown role for the thrombin receptor protease-activated receptor 1 in the lymphatic vasculature that promotes a similar change in junction morphology as seen in blood vessels, but with a disparate effect on lymphatic function.
肺淋巴脉管系统在炎症和水肿情况下能够显著增加淋巴引流；然而，驱动这一过程的机制尚不清楚。在此我们表明，肺损伤会使肺淋巴内皮细胞连接的构型从连续的“拉链式”构型转变为不连续且具有渗透性的“纽扣式”构型。尽管与在渗漏和功能失调的血管中常见的连接变化相似，但我们发现淋巴脉管系统向纽扣式连接的转变具有相反的效果，导致肺淋巴引流增加。从机制上讲，我们证明在肺损伤模型中肺淋巴纽扣式连接的形成依赖于凝血酶受体蛋白酶激活受体1，这是一种已知的血管通透性介质。这些结果揭示了凝血酶受体蛋白酶激活受体1在淋巴脉管系统中以前未知的作用，该作用促进了与血管中所见相似的连接形态变化，但对淋巴功能有不同的影响。
