12/23/2025
Physician scientists discover how TRPV4 prevents severe lung injuries during pneumonia
Cleveland Clinic pulmonologist Rachel Scheraga, MD, has discovered how deficiencies in a key molecule called TRPV4 can turn infection-fighting white blood cells into drivers of life-threatening lung inflammation. The discovery, published in Science Signaling, marks a significant step for developing new treatments for conditions lacking effective options.
During serious microbial infections, the cells in our lungs can be physically damaged by inflammation and microbes. Dr. Scheraga’s lab previously found that white blood cells can sense these damaged areas of the lung. Although our white blood cells cause inflammation to support fighting off the infection, our immune systems can go overboard and damage already vulnerable and wounded tissue.
Dr. Scheraga treats many patients whose lungs become seriously injured from overactive white blood cells. Some of these injuries can cause chronic inflammatory conditions and others, including acute respiratory distress syndrome (ARDS), are immediate and life-threatening. ARDS has a survival rate of 50%. None of the more serious injuries have many options beyond supportive care, including ventilation, turning the patient to lie on their chest or using external life support.
“We can try to prescribe anti-inflammatory agents like steroids, but these treatments have mixed results and are hard to predict,” says Dr. Scheraga, who leads a research program in the department of Inflammation and Immunity. “What we really need are new drugs to reverse serious inflammation and injury in the lung, and relevant targets for those drugs.”
Our immune systems regulate their activity using molecules like TRPV4 to block inflammation, but little is known about how and why this process works. Dr. Scheraga’s team found that TRPV4 molecules help prevent excessive inflammation during infection by binding to a complex of molecules in the NF-κB pathway. This pathway is a master regulator of inflammatory signaling. This process is activated when the immune system senses bacteria through Toll-like receptors. When lung injury occurs, TRPV4 senses the injured tissue, the immune system spirals into overdrive, worsening lung injuries.
“It used to be very popular to try and develop anti-inflammatory drugs that directly block NF-κB, but that causes lots of off-target effects,” Dr. Scheraga explains.
Dr. Scheraga and her team hypothesize drugs designed to enhance TRPV4’s interactions with NF-κB could help prevent or reverse lung injury in pneumonia patients. Investigators are currently validating the initial findings in human samples isolated from fluid in the lungs of patients undergoing treatment for pneumonia.
"Now that we know immune cells use TRPV4 when interacting with an injured tissue, we might be able to target it and stop chronic inflammation right at the epicenter,” Dr. Scheraga says.
