Attenuation of Lipopolysaccharide-Induced Acute Lung Injury by Hispolon in Mice, Through Regulating the TLR4/PI3K/Akt/mTOR and Keap1/Nrf2/HO-1 Pathways, and Suppressing Oxidative Stress-Mediated ER Stress-Induced Apoptosis and Autophagy

Nutrients. 2020 Jun 10;12(6):1742. doi: 10.3390/nu12061742.

Abstract

The anti-inflammatory effect of hispolon has identified it as one of the most important compounds from Sanghuangporus sanghuang. The research objectives were to study this compound using an animal model by lipopolysaccharide (LPS)-induced acute lung injury. Hispolon treatment reduced the production of the pro-inflammatory mediator NO, TNF-α, IL-1β, and IL-6 induced by LPS challenge in the lung tissues, as well as decreasing their histological alterations and protein content. Total cell number was also reduced in the bronchoalveolar lavage fluid (BALF). Moreover, hispolon inhibited iNOS, COX-2 and IκB-α and phosphorylated IKK and MAPK, while increasing catalase, SOD, GPx, TLR4, AKT, HO-1, Nrf-2, Keap1 and PPARγ expression, after LPS challenge. It also regulated apoptosis, ER stress and the autophagy signal transduction pathway. The results of this study show that hispolon regulates LPS-induced ER stress (increasing CHOP, PERK, IRE1, ATF6 and GRP78 protein expression), apoptosis (decreasing caspase-3 and Bax and increasing Bcl-2 expression) and autophagy (reducing LC3 I/II and Beclin-1 expression). This in vivo experimental study suggests that hispolon suppresses the LPS-induced activation of inflammatory pathways, oxidative injury, ER stress, apoptosis and autophagy and has the potential to be used therapeutically in major anterior segment lung diseases.

Keywords: ER stress; HO-1; LPS; Nrf-2; anti-inflammation; apoptosis; hispolon.

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / genetics*
  • Animals
  • Anti-Inflammatory Agents
  • Apoptosis / drug effects*
  • Autophagy / drug effects*
  • Catechols / pharmacology*
  • Catechols / therapeutic use
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / drug effects
  • Heme Oxygenase-1 / metabolism
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lipopolysaccharides / adverse effects
  • Male
  • Membrane Proteins / metabolism
  • Mice, Inbred ICR
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / drug effects*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phytotherapy
  • Proto-Oncogene Proteins c-akt / isolation & purification*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Toll-Like Receptor 4 / metabolism*

Substances

  • Anti-Inflammatory Agents
  • Catechols
  • Endoplasmic Reticulum Chaperone BiP
  • Hspa5 protein, mouse
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Lipopolysaccharides
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Toll-Like Receptor 4
  • hispolon
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases