A receptor protein present in immune cells is a potential target for treating pulmonary hypertension (PH), according to a new study. The findings — based on patient lung tissue and animal experiments – showed a link between low levels of Toll-like receptor 3 (TLR3) and the disease.
Published in the American Journal of Respiratory and Critical Care Medicine in an article titled “Toll-like Receptor 3 is a Therapeutic Target for Pulmonary Hypertension,” the study was led by researchers at Virginia Commonwealth University and the University of Sheffield, U.K.
TLR3 receptors (proteins that bind a cell to chemical signals from outside the cell) are mostly found on immune cells, and they recognize and bind double-stranded RNA — a nucleic acid (like DNA) that contains genetic information, and is carried by certain viruses and released by damaged cells.
According to previous findings, TLR3 protects cells of blood vessels from undergoing programmed cell death, and so work to potentially prevent coronary arteries from becoming blocked, which may cause PH.
By analyzing lung tissue samples from patients and animal models, researchers studied the role of TLR3 in PH and potential treatment strategies.
A first tissue analysis showed that lung tissue and blood vessels from PH patients had low levels of TLR3.
To test the protective function of TLR3, researchers next induced PH in mice lacking TLR3, and found that the loss of this receptor increased the severity of PH. As a consequence of TLR3 loss, double-stranded RNA bound to different RNA-sensing receptors in cells lining lung blood vessels; this triggered programmed cell death in the blood vessels, followed by their constriction and blockage, and, subsequently, the development of PH.
In a final in vivo experiment, researchers gave rats high doses of a molecule that is structurally similar to double-stranded RNA and known to interact with TLR3. They found that the molecule increased the levels of TLR3 and eased PH severity.
“We found that stimulation with high levels of man-made RNA molecules increased expression of TLR3 and reduced pulmonary hypertension in animal models,” Laszlo Farkas, MD, the study’s senior author and a assistant professor in the Virginia Commonwealth’s School of Medicine, said in a university news release written by Leah Small.
“Our high-dose RNA treatment triggered an anti-inflammatory response that prompted TLR3 production,” Farkas added.
Overall, the team identified a new role for TLR3 in PH “based on the findings that reduced expression of TLR3 contributes to endothelial apoptosis [programmed cell death] and pulmonary vascular remodeling,” the researchers wrote. (Endothelial cells line the inside of blood vessels.)
Farkas believes that these findings could augment PH treatments that otherwise are of limited effectiveness.
“Follow-up studies are required to rule out potential side effects, but we believe that TLR3 signaling may be a novel avenue to complement existing treatment strategies for pulmonary hypertension,” he concluded.
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