title: Oxidant-induced corticosteroid unresponsiveness in human bronchial epithelial cells.
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-α-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.
authors: Laboratory of Allergology & Pulmonary Diseases, Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, , Groningen, The Netherlands.
authors: Irene
authors: I
authors: Heijink
authors: Antoon
authors: A
authors: van Oosterhout
authors: Nathalie
authors: N
authors: Kliphuis
authors: Marnix
authors: M
authors: Jonker
authors: Roland
authors: R
authors: Hoffmann
authors: Eef
authors: E
authors: Telenga
authors: Karin
authors: K
authors: Klooster
authors: Dirk-Jan
authors: DJ
authors: Slebos
authors: Nick
authors: N
authors: ten Hacken
authors: Dirkje
authors: D
authors: Postma
authors: Maarten
authors: M
authors: van den Berge
mesh_terms: D000328:Adult; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D001980:Bronchi / Q000166:cytology*; D019819:Budesonide / Q000627:therapeutic use; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology* / Q000627:therapeutic use; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects
chemical_list: D005938:Glucocorticoids; D016209:Interleukin-8; D019819:Budesonide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Airway Epithelium; Asthma; COPD Pharmacology; GM-CSF; Oxidative Stress