Lymph vessels on a chip reveal possible new drug target for lymphedema

WASHINGTON, D.C. —There’s no real cure for lymphedema, a painful accumulation of fluid in the arms and legs that afflicts more than 150 million people worldwide. Compression garments and anti-inflammatory drugs can ease the swelling, and electric pumps can push the fluid along, but neither provides a long-lasting solution. Now, researchers have found that a chemical similar to some glaucoma medicines alleviates symptoms of lymphedema in mice by targeting a specific protein, suggesting a new approach to treating the disease.

The lymphatic system extends throughout the body, with vessels that absorb protein-rich and white blood cell–filled fluid from tissues and transport it to lymph nodes. When the vessels can’t properly drain this fluid, it builds up in the tissue, causing lymphedema. Surgeries or cancer treatments such as radiation can bring on the condition, which can lead to a thickening and stiffening of the skin, fat buildup, and sometimes, cancer.

To look for better treatments for lymphedema, Esak Lee, a bioengineer at Cornell University, and his colleagues built a model of a lymphatic system on a chip, suspending human lymph vessel cells in collagen in a small polymer box. Using this system, the researchers identified a protein, integrin alpha-5, as potentially important to lymphedema. The protein normally sits inactive in the cell membranes of the tissue that makes up the lining of lymphatic vessels. But when the scientists simulated lymphedema by treating the vessels on the chip with molecules that signal inflammation, integrin alpha-5 became active and signaled cellular junctions to tighten and prevent the flow of lymph fluid.

Next, Lee and his team administered a compound that inactivated integrin alpha-5. This allowed vessels on the chip to drain lymph fluid—and it produced the same result when given to mice with induced lymphedema. The inhibitor is in the same class of compounds—known as Rho kinase inhibitors—as the drug Ripasudil, which is used in Japan to treat glaucoma and other eye-related conditions.

Lee reported the findings here this week at a joint meeting of the American Society for Cell Biology and the European Molecular Biology Organization. The work is not yet published, and the drug will have to undergo additional testing before anyone tries the approach in humans.

But Ryan Petrie, a cell biologist at Drexel University in Philadelphia, Pennsylvania, who was not involved in the study, thinks Lee’s lymphatics-on-a-chip model has promise for understanding the mechanism of integrin alpha-5 in lymphedema. “What struck me was how novel this was,” he says, noting that few groups have modeled lymphatic vessels this way in the past.