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Theophylline and dexamethasone in combination reduce inflammation and prevent the decrease in HDAC2 expression seen

Xue-Jiao Sun1,2, Zhan-Hua Li1,3, Yang Zhang1

  • 1Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China.

Experimental and Therapeutic Medicine
|April 10, 2020
PubMed
Summary

Combined theophylline and dexamethasone (Dex) treatment reduces inflammation in chronic obstructive pulmonary disease (COPD) models. This therapy reverses corticosteroid insensitivity by inhibiting the PI3K/Akt pathway and increasing histone deacetylase 2 (HDAC2) expression.

Keywords:
PI3K/Akt pathwaychronic obstructive pulmonary diseasecorticosteroid insensitivitydexamethasonetheophylline

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Area of Science:

  • Pulmonology
  • Pharmacology
  • Molecular Biology

Background:

  • Chronic obstructive pulmonary disease (COPD) involves lung inflammation, impaired function, and increased mortality.
  • Corticosteroid insensitivity hinders effective anti-inflammatory management in COPD.
  • Theophylline and glucocorticoids exhibit anti-inflammatory properties in respiratory conditions.

Purpose of the Study:

  • To investigate if combined theophylline and dexamethasone (Dex) treatment reduces cigarette smoke extract (CSE)-induced inflammation.
  • To determine if this combination prevents reduced histone deacetylase 2 (HDAC2) expression and inhibits the PI3K/Akt pathway.
  • To explore the relationship between this combined therapy and corticosteroid sensitivity in COPD models.

Main Methods:

  • Assessed corticosteroid sensitivity using the half-maximal inhibitory concentration (IC50) of Dex on tumor necrosis factor-α (TNF-α)-induced interleukin (IL)-8 release.
  • Utilized reverse transcription quantitative PCR and western blotting to measure HDAC2 expression and Akt phosphorylation in U937 cells treated with CSE.
  • Evaluated the effects of theophylline and Dex pre-treatment on CSE-induced inflammatory markers.

Main Results:

  • Theophylline and Dex pre-treatment significantly reduced CSE-induced IL-8 and TNF-α release.
  • Combined therapy reversed corticosteroid insensitivity in CSE-induced U937 cells and inhibited the PI3K/Akt pathway more effectively than theophylline alone.
  • CSE treatment reduced HDAC2 mRNA and protein expression, an effect attenuated by the combined therapy or theophylline alone.

Conclusions:

  • Pretreatment with theophylline and dexamethasone decreases CSE-induced inflammation in COPD models.
  • The combined therapy works by inhibiting the PI3K/Akt pathway and increasing HDAC2 protein expression.
  • This approach may offer a strategy to overcome corticosteroid insensitivity in COPD management.