Researchers have shown that the cell signaling molecule tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) may be a potential therapeutic target for pulmonary arterial hypertension (PAH).
Allan Lawrie (University of Sheffield, UK) and team report in the Journal of Experimental Medicine that TRAIL proved a potent stimulus for pulmonary vascular remodeling in human cells and rodent models. Moreover, antibody blockade or genetic deletion of TRAIL arrested the development of PAH in three rodent models.
Lawrie commented in a press statement: "This research opens up a new insight into the mechanisms of PAH and suggests that TRAIL is critical to this process. If we can interrupt this process by blocking the TRAIL pathway, we have the potential to stop the disease in its tracks and even reverse the damage already done."
A previous study by Lawrie et al demonstrated TRAIL immunoreactivity within pulmonary vascular lesions in patients with idiopathic PAH, and in animal models.
In the current study, Lawrie's team found that TRAIL messenger RNA (mRNA) expression was significantly increased in pulmonary artery smooth muscle cells explanted from the transplanted lungs of patients with idiopathic PAH and grown in vitro compared with cells from control non-PAH patients.
Anti-TRAIL antibody treatment of rodents with established PAH reversed pulmonary vascular remodeling by reducing proliferation and inducing apoptosis of vascular smooth muscle cells, improved hemodynamic indices, and significantly increased survival rates. Indeed, at 28 days, 100% of rodents on anti-TRAIL antibody therapy were alive compared with 80% of controls.
Shannon Amoils, Research Advisor at the British Heart Foundation commented: "TRAIL plays a role in [PAH] by driving the overproduction of cells lining the lungs' blood vessels. This overproduction of cells is one of the factors leading to high blood pressure in the lungs. "Importantly, the researchers show that in rodents, blocking TRAIL using an antibody dampens down this high cell turnover and reduces the disease severity. There is still a long way to go, but the hope is that the TRAIL antibody might be developed into a new treatment for patients in the future."
Lawrie remarked: "We are now actively pursuing a route to develop human antibodies as a potential new treatment for PAH, though this is likely to be several years from the clinic."
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