1β-Hydroxyalantolactone from Inulae Flos alleviated the progression of pulmonary fibrosis via inhibiting JNK/FOXO1/NF-κB pathway

1β-Hydroxyalantolactone, a novel sesquiterpene lactone (HAL) from Inulae Flos, inhibited TGF-β1-induced myofibroblast activation in vitro and bleomycin-induced lung fibrosis in vivo via regulating JNK/FOXO1/NF-κB pathway. [Display omitted] •The phenotypic high-content imaging was employed for screen...

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Published in:International immunopharmacology 2021-12, Vol.101 (Pt A), p.108339-108339, Article 108339
Main Authors: Yu, Bing, Jin, Xiao-Qing, Yu, Wen-Ying, Dong, Ying-Ying, Ying, Hua-Zhong, Yu, Chen-Huan
Format: Article
Language:English
Subjects:
Actin
Animals
Anisomycin
Antifibrotic Agents - isolation & purification
Antifibrotic Agents - therapeutic use
Apoptosis
Asthma
Bleomycin
Bronchitis
Cell apoptosis
Cell lines
Cough
Fibroblasts
Fibroblasts - drug effects
Fibrosis
Flavonoid
Flavonoids
Fluorescent Antibody Technique
Forkhead Box Protein O1 - antagonists & inhibitors
Forkhead Box Protein O1 - metabolism
FOXO1
FOXO1 protein
Humans
Interleukin 6
Inula - chemistry
JNK
Lactones
Lung diseases
Lungs
Male
MAP Kinase Signaling System - drug effects
mRNA
NF-κB protein
Pharmacology
Plant Extracts - isolation & purification
Plant Extracts - therapeutic use
Pulmonary fibrosis
Pulmonary Fibrosis - drug therapy
Pulmonary Fibrosis - metabolism
Rats
Rats, Sprague-Dawley
Reactive Oxygen Species - metabolism
Real-Time Polymerase Chain Reaction
Respiratory diseases
ROS
Sesquiterpene lactone
Sesquiterpene lactones
Sesquiterpenes - isolation & purification
Sesquiterpenes - therapeutic use
Signal Transduction - drug effects
Smad3 protein
Transforming growth factor-b1
Tumor necrosis factor-α
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Summary:1β-Hydroxyalantolactone, a novel sesquiterpene lactone (HAL) from Inulae Flos, inhibited TGF-β1-induced myofibroblast activation in vitro and bleomycin-induced lung fibrosis in vivo via regulating JNK/FOXO1/NF-κB pathway. [Display omitted] •The phenotypic high-content imaging was employed for screening antifibrotic compounds in the plants.•1β-hydroxyalantolactone (HAL) from I. Flos had obvious antifibrotic effects.•HAL induced apoptosis of fibroblast via reducing intracellular oxidative stress.•HAL inhibited fibroblast activation via regulating JNK/FOXO1/NF-κB pathway.•HAL improved bleomycin-induced lung fibrosis and inflammation in rats. Inulae Flos was widely distributed throughout Europe, Africa, and Asia, and was commonly used as a folk medicine in clinic for treating various respiratory diseases, including cough, asthma, bronchitis, pulmonary fibrosis, and pneumonia. However, the ingredients responsible for the pharmacology effects of I. Flos and the underlying mechanisms remain unclear. In this study, the effects of 16 known sesquiterpene lactones and flavonoids from I. Flos on TGF-β1-induced fibroblast activation were assessed by phenotypic high-content screening. Among those sixteen compounds, 1β-hydroxy alantolactone (HAL), the main characteristic sesquiterpene lactone from I. Flos, exhibited remarkable inhibitory activity. The further studies showed that HAL significantly inhibited the proliferation and induced the apoptosis of human fibroblast cell lines HELF and MRC-5 in a concentration-dependent manner. It also reduced intracellular ROS production, suppressed the mRNA expressions of E-cad, TGF-β1, Smad3, Col I, α-SMA and TNF-α, and downregulated protein expressions of α-SMA and F-actin. Furthermore, HAL significantly reduced the levels of HA, LN, PC-III and IV-C in serum, TNF-α and IL-6 in BALF, and TGF-β1, HYP and Col I in lung tissues of bleomycin (BLM)-treated rats. HAL significantly downregulated the expressions of p-JNK, FOXO1, p-p65, α-SMA, p-smad3 and Col I but upregulated p-FOXO1, which could be reversed by JNK agonist anisomycin. These results demonstrated that HAL induced the apoptosis of lung fibroblast cells activated by TGF-β1 and improved BLM-induced lung fibrosis in rats via inhibiting JNK/FOXO1/NF-κB pathway.
ISSN:1567-5769
1878-1705
DOI:10.1016/j.intimp.2021.108339