Inhibition of endoplasmic reticulum stress alleviates lipopolysaccharide-induced lung inflammation through modulation of NF-κB/HIF-1α signaling pathway

Sci Rep. 2013;3:1142. doi: 10.1038/srep01142. Epub 2013 Jan 28.

Abstract

Lipopolysaccharide (LPS) is involved in a variety of inflammatory disorders. Under stress conditions, endoplasmic reticulum (ER) loses the homeostasis in its functions, which is defined as ER stress. Little is known how ER stress is implicated in LPS-induced lung inflammation. In this study, effects of inhibition of ER stress on LPS-induced lung inflammation and transcriptional regulation were examined. An ER stress regulator, 4-phenylbutyrate (PBA) reduced LPS-induced increases of various ER stress markers in the lung. Furthermore, inhibition of ER stress reduced the LPS-induced lung inflammation. Moreover, LPS-induced increases of NF-κB and HIF-1α activity were lowered by inhibition of ER stress. These results suggest that inhibition of ER stress ameliorates LPS-induced lung inflammation through modulation of NF-κB/IκB and HIF-1α signaling pathway.

MeSH terms

  • Animals
  • Biomarkers
  • Cell Nucleus / metabolism
  • Cytokines / metabolism
  • Endoplasmic Reticulum Stress* / drug effects
  • Female
  • Gene Expression Regulation
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Inflammation Mediators / metabolism
  • Leukocytes, Mononuclear / metabolism
  • Lipopolysaccharides / adverse effects
  • Mice
  • NF-kappa B / metabolism*
  • Phenylbutyrates / pharmacology
  • Pneumonia / chemically induced
  • Pneumonia / metabolism*
  • Pneumonia / pathology
  • Protein Transport
  • Proteolysis
  • RNA Interference
  • Signal Transduction* / drug effects
  • Transcription Factor CHOP / metabolism
  • Unfolded Protein Response / drug effects

Substances

  • Biomarkers
  • Cytokines
  • Heat-Shock Proteins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • Phenylbutyrates
  • Transcription Factor CHOP
  • 4-phenylbutyric acid
  • molecular chaperone GRP78