Total flavonoids of Inula japonica alleviated the inflammatory response and oxidative stress in LPS-induced acute lung injury via inhibiting the sEH activity: Insights from lipid metabolomics.

Abstract

BACKGROUND:

Acute lung injury (ALI) is a severe respiratory disease characterized by diffuse lung interstitial and respiratory distress and pulmonary edema with a mortality rate of 35%-40%. Inula japonica Thunb., known as "Xuan Fu Hua" in Chinese, is a traditional Chinese medicine Inulae Flos to use for relieving cough, eliminating expectorant, and preventing bacterial infections in the clinic, and possesses an anti-pulmonary fibrosis effect. However, the effect and action mechanism of I. japonica on ALI is still unclear.

PURPOSE:

This study aimed to investigate the protective effect and underlying mechanism of total flavonoids of I. japonica (TFIJ) in the treatment of ALI.

STUDY DESIGN AND METHODS:

A mouse ALI model was established through administration of LPS by the intratracheal instillation. Protective effects of TFIJ in the inflammation and oxidative stress were studied in LPS-induced ALI mice based on inflammatory and oxidative stress factors, including MDA, MPO, SOD, and TNF-α. Lipid metabolomics, bioinformatics, Western blot, quantitative real-time PCR, and immunohistochemistry were performed to reveal the potential mechanism of TFIJ in the treatment of ALI.

RESULTS:

TFIJ significantly alleviated the interstitial infiltration of inflammatory cells and the collapse of the alveoli in LPS-induced ALI mice. Lipid metabolomics demonstrated that TFIJ could significantly affect the CYP2J/sEH-mediated arachidonic acid metabolism, such as 11,12-EET, 14,15-EET, 8,9-DHET, 11,12-DHET, and 14,15-DHET, revealing that sEH was the potential target of TFIJ, which was further supported by the recombinant sEH-mediated the substrate hydrolysis in vitro (IC50 = 1.18 μg/ml). Inhibition of sEH by TFIJ alleviated the inflammatory response and oxidative stress via the MAPK, NF-κB, and Nrf2 signaling pathways.

CONCLUSION:

These results demonstrated that TFIJ could suppress the sEH activity to stabilize the level of EETs, allowing the alleviation of the pathological course of lung injury in LPS-treated mice, which suggested that TFIJ could serve as the potential agents in the treatment of ALI.

• Authors: Juan Zhang, Min Zhang, Wen-Hao Zhang, Qi-Meng Zhu, Xiao-Kui Huo, Cheng-Peng Sun, Xiao-Chi Ma, Hai-Tao Xiao
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 107 Pg. 154380 (Dec 2022) ISSN: 1618-095X [Electronic] Germany
• PMID: 36150346 (Publication Type: Journal Article)
• Copyright: Copyright © 2022. Published by Elsevier GmbH.

Chemical References

• Expectorants
• Flavonoids
• Lipopolysaccharides
• NF-E2-Related Factor 2
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Arachidonic Acid
• Superoxide Dismutase

Topics

• Acute Lung Injury (chemically induced, drug therapy, metabolism)
• Animals
• Arachidonic Acid (metabolism)
• Expectorants (adverse effects)
• Flavonoids (pharmacology, therapeutic use)
• Inula
• Lipopolysaccharides (pharmacology)
• Lung
• Mice
• NF-E2-Related Factor 2 (metabolism)
• NF-kappa B (metabolism)
• Oxidative Stress
• Superoxide Dismutase (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)