Pirfenidone improves pulmonary hemodynamics and vascular remodeling in a rat model of pulmonary arterial hypertension (PAH), a new study published in Pulmonary Circulation found.

The study also found that the treatment decreased the cleavage of IL-1β and IL-18, which are products of the activation of NLRP3 inflammasome and play key roles downstream from NLRP3.

The authors of the study concluded that pirfenidone may exert its therapeutic effects by suppressing the activation of the NLRP3 inflammasome.


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The exact mechanism of action of pirfenidone is not known but the drug has antifibrotic, anti-inflammatory, and antioxidant properties. It is used to treat idiopathic pulmonary fibrosis. Research has suggested that it may also inhibit the activation of the NLRP3 inflammasome.

To test the hypothesis that pirfenidone may delay PAH progression by suppressing the activation of the NLRP3 inflammasome, a team of researchers led by Rolf M.F. Berger, MD, PhD, from the Centre for Congenital Heart Diseases, the University of Groningen in the Netherlands used a rat model of neointimal PAH.

Read more about the pathophysiology of PAH

The researchers measured inflammasome activation by NLRP3 immunostaining and Western blots for caspase-1, IL-1β, and IL-18 cleavage, and macrophage IL-1β secretion. 

They found that in “PAH rats, immunostaining of NLRP3 in pulmonary arterioles and caspase-1, IL-1β, and IL-18 cleavage in lung homogenates were increased compared to controls.” This, they said, reflects the activation of the NLRP3 inflammasome.

When they treated the rats with pirfenidone, pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary vascular remodeling were improved. Moreover, IL-1β and IL-18 cleavage, and macrophage IL-1β secretion decreased in vitro.

“Our studies show that [pirfenidone] ameliorates pulmonary hemodynamics and vascular remodeling in experimental PAH,” the researchers concluded.

Reference

Mavrogiannis E, Hagdorn QAJ, Bazioti V, et al. Pirfenidone ameliorates pulmonary arterial pressure and neointimal remodeling in experimental pulmonary arterial hypertension by suppressing NLRP3 inflammasome activation. Pulm Circ. Published online June 17, 2022. doi:10.1002/pul2.12101