Fluorofenidone protects mice from lethal endotoxemia through the inhibition of TNF-α and IL-1β release

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release proinflammatory factors like INF-alpha and IL-1 beta. Fluorofenidone (AKF-PD) is a novel pyridone agent, which exerts a strong antifibrotic effect. In this work, we showed that AKF-PD also exert an inhibitory effect on acute systemic inflammatory response. AKF-PD treatment significantly increased survival in animals with established endotoxemia. In addition, AKF-PD treatment significantly reduced circulating levels of TNF-alpha and IL-1 beta during endotoxemia. In macrophage cultures, AKF-PD inhibited the release of TNF-alpha and IL-1 beta in a dose-dependent manner. In conclusion, these results indicate that AKF-PD inhibits the release of the proinflammatory cytokines (TNF-alpha and IL-1 beta) and improves survival during lethal endotoxemia, which suggest this new pyridone agent can be a novel candidate for therapy of septic shock. (C) 2010 Elsevier B.V. All rights reserved.