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Fluorofenidone protects mice from lethal endotoxemia through the inhibition of TNF-alpha and IL-1beta release
Yiting Tang1, Bingxin Li, Nasui Wang
1Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Abstract:
The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release proinflammatory factors like TNF-alpha and IL-1beta. 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-1beta during endotoxemia. In macrophage cultures, AKF-PD inhibited the release of TNF-alpha and IL-1beta in a dose-dependent manner. In conclusion, these results indicate that AKF-PD inhibits the release of the proinflammatory cytokines (TNF-a and IL-1beta) and improves survival during lethal endotoxemia, which suggest this new pyridone agent can be a novel candidate for therapy of septic shock.
Insights
Fluorofenidone (AKF-PD) effectively treats endotoxemia by reducing inflammatory cytokines tumor necrosis factor-alpha (TNF-a) and interleukin-1beta (IL-1beta), significantly improving survival rates in septic shock models.
Area of Science:
- Immunology
- Pharmacology
Background:
- Sepsis pathogenesis involves bacterial endotoxin stimulating macrophages to release inflammatory cytokines like TNF-alpha and IL-1beta.
- Fluorofenidone (AKF-PD) is a novel pyridone agent known for its antifibrotic properties.
Purpose of the Study:
- To investigate the potential of AKF-PD in modulating acute systemic inflammatory responses.
- To evaluate AKF-PD's efficacy in treating endotoxemia and its impact on survival.
Main Methods:
- Animal models of established endotoxemia were treated with AKF-PD.
- Circulating levels of TNF-alpha and IL-1beta were measured.
- Macrophage cultures were used to assess AKF-PD's direct effect on cytokine release.
Main Results:
- AKF-PD treatment significantly increased survival rates in animals with endotoxemia.
- AKF-PD significantly reduced circulating TNF-alpha and IL-1beta levels.
- In vitro, AKF-PD inhibited TNF-alpha and IL-1beta release from macrophages in a dose-dependent manner.
Conclusions:
- AKF-PD demonstrates potent anti-inflammatory effects by inhibiting key pro-inflammatory cytokines.
- These findings suggest AKF-PD as a promising therapeutic candidate for managing septic shock.
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