PR1P Peptide Reduces Lung Cell Death, Tissue Damage in Emphysema, Preclinical Study Shows

PR1P, a small peptide able to increase the activity of vascular endothelial growth factor (VEGF) in cells lining the inside of blood vessels, can reduce lung cell death and tissue damage in a mouse model of emphysema, a study reports.

According to investigators, these findings highlight the therapeutic potential of PR1P for the treatment of emphysema and other lung diseases where VEGF signaling is affected.

The findings were reported in the study “PR1P Stabilizes VEGF and Upregulates its Signaling to Reduce Elastase Induced Murine Emphysema,” published in the American Journal of Respiratory Cell and Molecular Biology.

Emphysema is a severe form of chronic obstructive pulmonary disease (COPD) characterized by the progressive damage and destruction of alveoli, the small air-filled sacs inside the lungs that are essential for breathing.

In addition to the gradual destruction of lung cells forming the alveoli, disease progression is thought to be driven by the dysregulation of a signaling cascade controlled by VEGF — a protein that plays a key role in controlling the formation of new blood vessels and keeping lung tissue healthy.

“VEGF is found at high levels in the normal lung — more than 500 times the levels seen in blood plasma,” Avner Adini, PhD, researcher at Boston Children’s Hospital and first author of the study, said in a press release.

“VEGF levels tend to become dramatically disrupted during lung disease, but return to normal during recovery. In emphysema, VEGF activity is low,” Adini added.

To normalize the levels and restore the activity of VEGF in the lungs, investigators first thought of administering the protein directly as a form of treatment for emphysema.

However, this strategy proved to be unfeasible, as experiments in animal models had shown that VEGF has a very short half-life in the body and can trigger a series of potentially dangerous side effects, including low blood pressure. Of note, half-life is the time it takes for the levels of a drug or compound circulating in the body to drop to half of the original amount given.

This led the team to look for alternative methods that could be used to increase the activity of VEGF that did not involve administering the protein directly.

The team then developed a small peptide, called PR1P, made up of 12 amino acids (protein building blocks) normally used by a different protein (prominin-1) to bind to VEGF.

In a previous study, the team found that in endothelial cells — those lining the inside of blood vessels — PR1P enhances the binding of VEGF to its receptors, and thus its activity.

To investigate its therapeutic potential in emphysema, the researchers treated human lung cells cultured in a lab dish and mouse models of the disease with the PR1P peptide. In both cases, PR1P increased VEGF signaling and prevented the protein from being destroyed.

The team also discovered that in mice, inhalation of the peptide was sufficient to increase the levels of VEGF found in the lungs within 30 minutes. Moreover, 24 hours later, the levels of VEGF in these animals remained two-times higher compared to those seen in vehicle-treated (control) mice.

Additionally, PR1P also lowered lung cell death — one of the hallmarks of emphysema — both in lab-cultured cells and in cells in the animals’ lungs.

Finally, the researchers showed that PR1P was able to reduce lung injury in mice with emphysema that were followed for up to 21 days without triggering any undesirable side effects.

“Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation,” they wrote.

These other diseases include, for instance, acute respiratory distress syndrome (ARDS), a common and severe lung disease in which the team is already testing PR1P.

“We are now also seeing dramatic lung-preserving and anti-inflammatory effects of inhaled PR1P in mice exposed to multiple diverse toxins that induce lung injury in ARDS models,” Adini said.