Total terpenoids of Inula japonica activated the Nrf2 receptor to alleviate the inflammation and oxidative stress in LPS-induced acute lung injury

Phytomedicine. 2022 Dec:107:154377. doi: 10.1016/j.phymed.2022.154377. Epub 2022 Aug 3.

Abstract

Background: Acute lung injury (ALI) is a life-threatening lung disease and characterized by pulmonary edema and atelectasis. Inula japonica Thunb. is a commonly used traditional Chinese medicine for the treatment of lung diseases. However, the potential effect and mechanism of total terpenoids of I. japonica (TTIJ) on ALI remain obscure.

Purpose: This study focused on the protective effect of TTIJ on lipopolysaccharide (LPS)-induced ALI in mice and its potential mechanism.

Study design and methods: A mouse model of ALI was established by intratracheal instillation of LPS to investigate the protective effect of TTIJ. RNA-seq and bioinformatics were then performed to reveal the underlying mechanism. Finally, western blot and real-time qPCR were used to verify the effects of TTIJ on the inflammation and oxidative stress.

Results: TTIJ notably attenuated LPS-induced histopathological changes of lung. The RNA-seq result suggested that the protective effect of TTIJ on LPS-induced ALI were associated with the Toll-like receptor 4 (TLR4) and nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathways. Pretreatment with TTIJ significantly reduced the inflammation and oxidative stress via regulating levels of pro-inflammatory and anti-oxidative cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), and glutathione (GSH), in LPS-induced ALI mice. TTIJ treatment could suppress the cyclooxygenase-2 (COX-2) expression level and the phosphorylation of p65, p38, ERK, and JNK through the inactivation of the MAPK/NF-κB signaling pathway in a TLR4-independent manner. Meanwhile, TTIJ treatment upregulated expression levels of proteins involved in the Nrf2 signaling pathway, such as heme oxygenase-1 (HO-1), NAD(P)H: quinoneoxidoreductase-1 (NQO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modifier subunit (GCLM), via activating the Nrf2 receptor, which was confirmed by the luciferase assay.

Conclusion: TTIJ could activate the Nrf2 receptor to alleviate the inflammatory response and oxidative stress in LPS-induced ALI mice, which suggested that TTIJ could serve as the potential agent in the treatment of ALI.

Keywords: Acute lung injury (ALI); Inflammation; Inula japonica; Nrf2; Oxidative stress; TLR4; Total terpenoids.

MeSH terms

  • Acute Lung Injury* / chemically induced
  • Acute Lung Injury* / drug therapy
  • Acute Lung Injury* / metabolism
  • Animals
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Glutamate-Cysteine Ligase / metabolism
  • Glutathione / metabolism
  • Heme Oxygenase-1 / metabolism
  • Inflammation / drug therapy
  • Inflammation / pathology
  • Interleukin-6 / metabolism
  • Inula*
  • Lipopolysaccharides / pharmacology
  • Mice
  • NAD / metabolism
  • NAD / pharmacology
  • NAD / therapeutic use
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • Oxidative Stress
  • Superoxide Dismutase / metabolism
  • Terpenes / pharmacology
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cytokines
  • Interleukin-6
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Terpenes
  • Toll-Like Receptor 4
  • Tumor Necrosis Factor-alpha
  • NAD
  • Heme Oxygenase-1
  • Cyclooxygenase 2
  • Superoxide Dismutase
  • Glutamate-Cysteine Ligase
  • Glutathione