Acute Respiratory Distress Syndrome (ARDS) is an often fatal condition where fluid leaks from the blood vessels into the lungs. The resulting cycle of inflammation and leaking fluid is vicious, with the patient feeling like they are drowning in their own fluids.
Researchers with the University of Illinois at Chicago have discovered a mechanism at the cellular level that forms a bond between the cells lining blood vessels, creating a leak-proof barrier. UIC researchers, led by Asrar Malik, Schweppe Family Distinguished Professor, and head of pharmacology, found they could activate the mechanism, causing cells to tighten in mice using a small molecule called Fg4497.
The scientists found that if mice were given the Fg4497 compound and then exposed to an infection causing fluids to leak from blood vessels into the lungs, they had a higher survival rate than those mice not treated with the Fg4497. Their findings were reported in the Journal of Clinical Investigation.
In patients with ARDS, fluid builds up in the alveoli, tiny air sacs in the lungs. More fluid in the lungs means less oxygen is able to get into the blood stream, resulting in the body’s organs not getting the oxygen needed to function. Currently, the only treatment is supportive care, like artificial ventilation. There are very few therapies that can reverse ARDS.
“In ARDS, our body’s own immune response becomes a major problem,” says Dr. Jalees Rehman, associate professor of pharmacology and medicine in the UIC College of Medicine and one of the lead authors of the study.
In the body’s normal and healthy immune response to infection, the barrier between blood vessels at the cellular level loosens temporarily. This allows white blood cells to leave the bloodstream to fight bacteria or viruses causing infection. But sometimes, in a severe respiratory infection, the barrier is slow to close back up. Dr. Rehman says the leakiness then becomes a problem, especially in the lungs.
The researchers studied the mechanics that govern cell-to-cell contact. They are called “adherens junctions.” They knew that a molecule called VE-PTP was necessary in stabilizing adherens junctions. Simply put, the scientists found that with low oxygen levels in the lungs, the oxygen-sensitive gene regulator HIF2alpha is activated, which in turn leads to increased levels of VE-PTP.
According to the research team, “mice that lacked HIF2alpha had much lower levels of VE-PTP and had much leakier blood vessels than mice that can make HIF2alpha.” Mice were exposed to bloodstream infections, after which they received a drug that produces low oxygen levels, Amazingly, the levels of HIF2alpha and VE-PTP in their bloodstream rose, and their blood vessels became less leaky. Survival rates were much higher than the mice not receiving the drug.
