Sildenafil May Treat PH by Limiting Cells That Induce Remodeling and Inflammation

Sildenafil appears to treat pulmonary hypertension (PH) by reducing the recruitment of bone marrow (BM)-derived progenitor cells, cells now being seen as potential key drivers of lung remodeling and inflammation in diseases that include PH.

The study, “Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells,” was published in the Journal of Cellular and Molecular Medicine.

Chronic hypoxia, or the chronic lack of oxygen in lung tissue, is an important factor in the development of PH. The disease is characterized by vascular remodeling, which ultimately leads to an increase in pulmonary arterial pressure. Previous studies showed that lung hypoxia-induced vascular remodeling works to recruit a specific type of cell, BM-derived progenitor cells. Several studies also suggest these cells contribute considerably to PH development.

Sildenafil, a drug that inhibits an enzyme called phosphodiesterase-5 (PDE-5), is used with success to treat PH. But its mode of action is still unclear. (The drug is FDA-approved in the U.S., and sold under the brand name Revatio.)

Researchers investigated whether the therapeutic benefits of sildenafil in PH are linked to a reduced recruitment of BM-derived progenitor cells. The team induced pulmonary remodeling in rats by exposing the animals to conditions of chronic hypoxia (10% oxygen) for two weeks. This resulted in BM-derived progenitor cells moving toward the lungs. Rats were then treated with either sildenafil (1.4 mg/kg/day) or with a saline solution (placebo controls) during the chronic hypoxia period. An additional group of rats, also used as controls, was maintained in normal oxygen conditions (21% oxygen) with no treatment.

Researchers observed, as expected, positive effects of sildenafil treatment: reduced right ventricle systolic pressure (by which the heart drives blood through the pulmonary valve into the lungs) and right ventricular hypertrophy (increase in heart’s ventricle size). Importantly, they saw that sildenafil treatment also reduced the number of BM-derived progenitor cells in the pulmonary tissue.

These results suggest that sildenafil may lessen chronic hypoxia-induced pulmonary vascular remodeling and dysfunction by working against the recruitment of BM-derived progenitor cells into the lungs. Since these cells are increasingly recognized for having a major role in PH — inducing lung remodeling and inflammation — reducing these cells’ numbers is a potential therapeutic strategy for PH.