A protein called PAR1 helps lymphatic vessels structurally transform to boost fluid drainage and support healing when the lungs are injured according to researchers from Weill Cornell Medicine. Injury—whether by infection, toxins, or trauma—can cause fluid buildup in the lungs, making it hard to breathe. In response, the body's lymphatic system, a network of vessels, tissues and organs, ramps up to clear inflammation. Excess fluid called lymph is removed from the body's tissues and returned to the blood for disposal. But the underlying mechanism of this process was unknown.
The study, published July 17 in Nature Cardiovascular Research, demonstrated that PAR1 triggers a change in the spaces between endothelial cells lining the inside of the lymphatic vessels of the lungs. This transformation makes the vessels permeable, so they can absorb more fluid and immune cells—a response distinct from blood vessels, where similar changes result in leakage and disease.
"These junctions govern how lymphatic vessels are able to perform fluid and cell uptake," said the study's principal investigator Dr. Hasina Outtz Reed , assistant professor of pulmonary and critical care medicine at Weill Cornell Medicine. "A better understanding of the molecular pathways that govern lung lymphatics could guide the treatment of various lung diseases."
The paper's first author, Dr. Chou Chou , instructor in medicine at Weill Cornell Medicine, and Camila Ceballos Paredes, a summer undergraduate researcher in the Outtz Reed Lab contributed to the research.
"Seeing countless patients with severe lung injury as a medical resident five years ago made me wonder why we still don't have targeted therapies for them," said Dr. Chou who is also a pulmonologist at NewYork-Presbyterian/Weill Cornell Medical Center. "We hope this research gives us a more complete picture of the lungs during severe injury and opens new avenues for therapies."
Button and Zipper Junctions
In the lungs, lymphatics are responsible for not only clearing fluid, but also moving immune cells around, maintaining stable conditions or homeostasis, and helping to respond to injury and inflammation. "Despite their critical role, lymphatics have been historically overlooked until recently, and lung lymphatics have been particularly understudied," said Dr. Outtz Reed, who is also a pulmonologist at NewYork-Presbyterian/Weill Cornell Medical Center.
Using mouse models, Dr. Outtz Reed and her colleagues observed how junctions between endothelial cells—described as buttons and zippers—change in the lungs' lymphatic vessels.
Button junctions are discontinuous. "You can think about buttons on a shirt," Dr. Outtz Reed explained. "Your fingers can go between the buttons and through the open flaps of fabric." This permeability allows lymphatic vessels to take up fluid and cells. In contrast, zipper junctions are like the zipper on a hoodie with tight spaces in between endothelial cells that don't allow fluid to enter the lymphatic vessel.
"One of the more surprising findings was that a large percentage of the lung lymphatic endothelial cells were zipped," Dr. Outtz Reed said. "But in response to injury, zippered junctions in the lungs can rapidly reorganize to be buttoned, aiding in fluid uptake."
The researchers showed that without PAR1, the lymphatic vessels stayed stuck in zipper mode—even when the lungs were inflamed. As a result, fluid drainage slowed down, and more immune cells were left behind in the lungs. Delving further into the transformation, they discovered that the zipper-to-button switch was caused by a biochemical signal.
Impact on Therapeutics
These findings suggest that drugs targeting PAR1, for instance in cardiovascular diseases or cancer progression, will have to consider the competing effects on blood vessels and lymphatic vessels. Therapies that globally block PAR1 could impair protective lymphatic responses in lung injury, which has implications in inflammatory lung diseases. "A lot of clinical trials targeting PAR1 have been unsuccessful. We think, in part, this may be due to the lymphatic vasculature, which also expresses this receptor, but responds to the drug in completely different ways than intended," Dr. Outtz Reed said.
Moving forward, Dr. Outtz Reed plans to explore how the changes in lymphatic junctions impact the lungs' response to infectious agents such as viruses and bacteria. She will also investigate how to target PAR1 on the lymphatics while sparing the blood vessels.
This work was supported by the National Institutes of Health grants R01 HL16299, R35 NS111619, NS39419, and T32 HL134629-Stout-Delgado; James Hilton Manning and Emma Austin Manning Foundation; Burroughs Wellcome Weill Cornell and the Stony Wold-Herbert Research Grant.
