Fluorofenidone protects mice from lethal endotoxemia through the inhibition of TNF-alpha and IL-1beta release.
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.
Division of Nephrology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
Yiting
Y
Tang
Bingxin
B
Li
Nasui
N
Wang
Yanyun
Y
Xie
Linghao
L
Wang
Qiongjing
Q
Yuan
Fangfang
F
Zhang
Jiao
J
Qin
Zhangzhe
Z
Peng
Wangbin
W
Ning
Ling
L
Wang
Gaoyun
G
Hu
Jing
J
Li
Lijian
L
Tao
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D015536:Down-Regulation; D019446:Endotoxemia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011728:Pyridones / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000378:metabolism
C511655:5-methyl-1-(3-fluorophenyl)-2-(1H)-pyridone; D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha