Researchers UMCG: Accelerated aging of lung vessels explains progression of lung disease PAH

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Researchers at the UMCG have discovered that accelerated aging of lung vessels explains why the deadly lung disease worsens PAH (pulmonary arterial hypertension) in patients. They also researched a new therapy that can treat this disease. An experimental anti-aging agent was used for this.

PAH

PAH is a rare, chronic lung disease. In the Netherlands, about 800 people are diagnosed with pulmonary arterial hypertension. Lung vessels slowly close in patients with PAH. This causes high blood pressure in the lungs.

PAH is a deadly disease that can also present in childhood, such as in children with congenital heart disease. In very young children, surgery for the heart defect can prevent and even reverse the progression of PAH.

However, if the diagnosis is made (too) late or the surgery takes place too late, PAH will lose this ‘reversibility’ and blood pressure in the lungs will continue to rise. This eventually leads to heart failure at a young age.

There are currently no treatments that can cure PAH.

Presence of rapidly aged cells

The research group of the UMCG / University of Groningen, which was led by Prof. Rolf Berger and Dr. Beatrijs Bartelds, mimicked a congenital heart defect in rats. The researchers saw that these rats developed a form of PAH that resembles the disease in humans, including a reversible and irreversible phase.

The researchers then, in collaboration with Stanford University, compared the genetic profiles of these rats, and they were found to differ essentially.

Under the microscope, it was found that the vessels of rats with irreversible PAH contain increased numbers of so-called ‘senescent cells’: cells that have accelerated aging and have lost their normal function. These cells cannot be removed by the body because they are resistant to normal programmed cell death.

Moreover, because these cells continuously excrete inflammatory factors, the accumulation of these aged cells leads to the stiffening and accelerated closure of the blood vessels in the lung.

Treatment with anti-aging agent

It is the first time that the presence of these aged cells is first associated with the irreversibility of PAH. The researchers then wondered whether removing these cells could help treat PAH.

This is possible with an experimental anti-aging agent, ABT-263. This kills the obsolete cells in the lung vessels, while the healthy cells can multiply again to repair the vessels.

The researchers gave ABT-263 to the rats with irreversible PAH, and showed that the vessels got through again and blood pressure in the lungs dropped. In addition, new, healthy vessels also appeared to develop after treatment.

“It has been known since the 1950s that PAH has reversible and irreversible phases,” says UMCG researcher Diederik van der Feen. “These results provide the first insight into why the disease becomes irreversible.”

Professor Marlene Rabinovitch of Stanford University (USA) adds that “the mechanism of reversibility is one of the major unresolved questions in PAH research, and this study provides important clues.”

The findings were published Thursday in the scientific journal Science Translational Medicine.

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