Pirfenidone suppresses tumor necrosis factor-alpha, enhances interleukin-10 and protects mice from endotoxic shock

by Selleckchem | Apr 12 2023

A new experimental drug, pirfenidone (5-methyl-1-phenyl-1H-pyridine-one; S-7701), has been reported to have beneficial effects for the treatment of certain fibrotic diseases. We investigated the anti-inflammatory properties in murine endotoxic shock to determine the pharmacological characteristics. The present study describes the prophylactic effect, cytokine regulatory profiles and therapeutic effect of pirfenidone in murine endotoxic shock, which was induced in mice using an intraperitoneal (i.p.) injection of lipopolysaccharide and D-galactosamine. First, we examined the prophylactic effect and cytokine regulatory profiles. A single oral administration of pirfenidone prior to lipopolysaccharide/D-galactosamine challenge inhibited the production of circulating tumor necrosis factor-alpha (TNF-alpha), interleukin-12 and interferon-gamma, markedly enhanced that of interleukin-10, and offered protection from subsequent lethal symptoms in a dose-dependent manner. Second, we examined the therapeutic effect. A single oral administration of pirfenidone 1, 2, 3, 4 and 5 h post lipopolysaccharide/D-galactosamine challenge provided protection against lethal shock in a time-dependent manner. At the histopathological level, apoptotic positive cells were found to be suppressed in the liver. The transforming growth factor (TGF)-beta1 level was markedly elevated in the liver of lipopolysaccharide/D-galactosamine-challenged mice, suppressed in pirfenidone-treated mice. These findings may offer an alternative for both protective and therapeutical treatment of several human acute or chronic inflammatory diseases by pirfenidone.

Comments：

The study investigated the potential of pirfenidone, a new experimental drug, to provide prophylactic and therapeutic benefits for murine endotoxic shock induced by lipopolysaccharide and D-galactosamine. The results showed that a single oral administration of pirfenidone prior to lipopolysaccharide/D-galactosamine challenge inhibited the production of pro-inflammatory cytokines and enhanced the production of interleukin-10, offering protection from subsequent lethal symptoms in a dose-dependent manner.

Moreover, a single oral administration of pirfenidone post lipopolysaccharide/D-galactosamine challenge provided protection against lethal shock in a time-dependent manner. The study also found that pirfenidone suppressed apoptotic positive cells in the liver and markedly elevated the transforming growth factor (TGF)-beta1 level, which was found to be elevated in the liver of lipopolysaccharide/D-galactosamine-challenged mice.

These findings suggest that pirfenidone may offer an alternative for both protective and therapeutic treatment of several human acute or chronic inflammatory diseases. However, further studies are necessary to determine the safety and efficacy of pirfenidone in human subjects.