Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells

Irene Heijink*, Antoon van Oosterhout, Nathalie Kliphuis, Marnix Jonker, Roland Hoffmann, Eef Telenga, Karin Klooster, Dirk-Jan Slebos, Nick ten Hacken, Dirkje Postma, Maarten van den Berge

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

43 Citations (Scopus)

Abstract

Background We hypothesised that increased oxidative stress, as present in the airways of asthma and chronic obstructive pulmonary disease (COPD) patients, induces epithelial damage and reduces epithelial responsiveness to suppressive effects of corticosteroids on proinflammatory cytokine production and barrier function.

Methods We induced oxidative stress by H2O2 and/or cigarette smoke extract (CSE) in human bronchial epithelial 16HBE cells and primary bronchial epithelial cells (PBEC) derived by brushings from asthma patients, COPD patients, and smoking and non-smoking control individuals. We investigated effects of budesonide on barrier function (electrical resistance) and TNF-alpha-induced proinflammatory cytokine production (IL-8/CXCL8, granulocyte macrophage-colony stimulating factor (GM-CSF)).

Results We observed that H2O2 and CSE reduce epithelial resistance. Budesonide significantly counteracted this effect, likely by protection against epidermal growth factor receptor-dependent cell-cell contact disruption. Furthermore, budesonide suppressed proinflammatory cytokine production. H2O2 pretreatment reduced this effect of budesonide on cytokine production in both 16HBE cells and PBECs. Importantly, PBECs from asthma and COPD patients were less sensitive to budesonide with respect to cytokine production and barrier function than PBECs from control subjects.

Conclusions Together, our data indicate that budesonide suppresses epithelial proinflammatory responses and barrier dysfunction and that oxidative stress reduces these effects in airway epithelium from asthma and COPD patients. Therefore, restoration of corticosteroid responsiveness in asthma and COPD may act to improve the airway epithelial barrier.

Original languageEnglish
Pages (from-to)5-13
Number of pages9
JournalThorax
Volume69
Issue number1
DOIs
Publication statusPublished - Jan-2014

Keywords

  • OBSTRUCTIVE PULMONARY-DISEASE
  • NECROSIS-FACTOR-ALPHA
  • AIRWAY INFLAMMATION
  • OXIDATIVE STRESS
  • CIGARETTE-SMOKING
  • BARRIER FUNCTION
  • E-CADHERIN
  • ASTHMA
  • GLUCOCORTICOIDS
  • INSENSITIVITY

Cite this