Naftopidil Inhibits Proliferation of Human Lung Fibroblasts and Reduces Lung Fibrosis in Mice, Study Finds

Santiago Gisler avatar

by Santiago Gisler |

Share this article:

Share article via email
metabolic pathway

Naftopidil treatment causes growth arrest of human lung fibroblasts and reduces fibrotic lesions in mice with idiopathic pulmonary fibrosis (IPF), a study shows.

The findings of the study, “Naftopidil reduced the proliferation of lung fibroblasts and bleomycin‐induced lung fibrosis in mice,” were published in the Journal of Cellular and Molecular Medicine.

IPF is characterized by the proliferation of fibroblasts and myofibroblasts (the cells responsible for fibrosis), and their production and deposition of extracellular matrix components — namely collagen and α-smooth muscle actin (α-SMA) proteins. As a result, the build-up of these components leads to damage of healthy lung structure, and to subsequent impaired lung function.

Although current treatment strategies for IPF inhibit lung fibrosis, the treatments often cause side effects, namely by affecting the nutritional status of patients.

Previous studies have shown that naftopidil (marketed as Flivas) — an inhibitor of α‐1 adrenoceptor (a receptor involved in smooth muscle contraction, among others) — has a growth inhibitory effect on prostate fibroblasts and prostate cancers. While the therapy inhibits prostate fibroblast proliferation with few side effects, little is known about its impact on lung fibroblasts and lung fibrosis.

Therefore, the researchers used both human lung fibroblast cell lines and bleomycin-induced lung fibrosis mouse models to evaluate the efficacy of naftopidil on lung fibroblast and lung fibrosis.

Lung fibrosis was induced in mice by treating them with bleomycin for 14 days, causing increased fibrotic lesions in alveolar areas and collagen accumulation. After 14 days, a group of mice received naftopidil, while another group did not (control mice).

The team found that bleomycin-treated mice receiving naftopidil showed both fewer fibrotic lesions and reduced collagen deposits than their control counterparts. Naftopidil treatment also resulted in fewer myofibroblasts expressing collagen I or α-SMA, compared with control mice.

“Naftopidil thus might attenuate lung fibrosis in part through decreasing α‐SMA expression and collagen expression in some fibroblasts,” the researchers wrote.

They next analyzed the levels of serum surfactant protein D (SP-D) — a serum protein used as a marker for lung fibrosis — in naftopidil-treated and control mice. While the administration of bleomycin alone increased the serum levels of SP-D, naftopidil-treated mice showed significantly reduced levels of the fibrotic marker.

The investigators further analyzed the mechanistic effects of naftopidil using different concentrations of the therapy on three different human cell lines of lung fibroblasts. They used two normal cell lines and one cell line derived from a patient with IPF.

Results showed that naftopidil treatment induced lower cell numbers in all three cell lines tested, which indicated inhibition of cell proliferation. By assessing the cycle profile of the cells, the team found that the cells arrested at specific non-dividing parts of the cell cycle, namely G0 (associated with cell-resting) or G1 (associated with RNA- and protein-production) phases.

“In conclusion, naftopidil inhibited cell proliferation in human lung fibroblasts by inducing G1 cell cycle arrest,” the researchers wrote. “Moreover, naftopidil reduced the extent of lung fibrosis and SP‐D production in bleomycin-induced lung fibrosis in mice.”

“Our study demonstrates the first evidence for the antifibrotic effect of naftopidil in lung fibrosis,” the team concluded.

The researchers, nonetheless, emphasized the need for further studies to test naftopidil’s effect on IPF.