Knowing How Esbriet Works for Pulmonary Fibrosis May Help Improve Safety, Efficacy

Researchers are a step closer to understanding the molecular mechanism of action in Esbriet (pirfenidone), the anti-fibrotic drug used to treat pulmonary fibrosis. Knowing how it works could help improve the safety and effectiveness of the drug that is currently used in very high doses to achieve therapeutic effectiveness, but which causes adverse side effects.

The study “Upregulation of RGS2: a new mechanism for pirfenidone amelioration of pulmonary fibrosis,” published in Respiratory Research, showed that Esbriet significantly increased the expression of a gene called G-protein signaling 2 (RGS2). The authors believe RGS2 contributes to the-anti fibrotic effect of Esbriet because of its endogenous anti-fibrotic action

The team of researchers led by Dr. Yaping Tu of the Department of Pharmacology at Creighton University School of Medicine, in Omaha, Nebraska, used a GeneChip microarray to screen for genes that were rapidly up regulated when human lung fibroblast cells were exposed to Esbriet.

Researchers found that treatment with Esbriet significantly increased the expression of RGS2 in healthy lung fibroblast cells grown in the laboratory and those isolated from patients with or without idiopathic pulmonary fibrosis (IPF).

The team also found that treatment with Esbriet inhibits the fibrotic effects of thrombin, a factor involved in the process of blood clotting. The same effect was observed when the RGS2 gene was over-expressed in human lung fibroblast cells in the laboratory.

On the contrary, the loss of RGS2 in mice worsened pulmonary fibrosis (induced with the drug bleomycin) and increased mortality. Additionally, Esbriet treatment reduced pulmonary fibrosis caused by bleomycin in healthy mice but not in mice where the RGS2 gene had been knocked out.

The results supported the idea that Esbriet exerts its anti-fibrotic effect through the RGS2 gene.

According to the authors: “Our data show that the beneficial effects of PFD in IPF can be explained at least in part by its ability to cause rapid RGS2 upregulation. Moreover, this RGS2 upregulation is both necessary and sufficient for the beneficial effects of PFD to be manifest, both in human cells and in mice.”

The research team concluded that their findings may help design more effective therapeutic strategies to stop and perhaps even partially reverse the progression of pulmonary fibrosis.