title: Apoptosis of airway epithelial cells induced by corticosteroids.
abstract: Damage to the airway epithelium is one prominent feature of chronic asthma. Corticosteroids induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, corticosteroid therapy does not necessarily reverse epithelial damage. We hypothesized that corticosteroids may induce airway epithelial cell apoptosis as one potential explanation for persistent damage. We tested this hypothesis in cultured primary central airway epithelial cells and in the cell line 1HAEo(-). Treatment with dexamethasone, beclomethasone, budesonide, or triamcinolone each elicited a time-dependent and concentration-dependent cell death. This cell death was associated with cleavage of nuclear chromatin, mitochondrial depolarization, cytochrome c extrusion, activation of caspase-9, and expression of phosphatidylserine on the outer cell membrane. Inhibitors of caspase activity blocked apoptotic cell death, as did overexpression of the apoptosis regulators Bcl-2 or Bcl-x(L). We demonstrated that CD95 ligation is not essential for the corticosteroid-induced apoptosis in airway epithelial cells. These data demonstrate that corticosteroids induce apoptotic cell death of airway epithelium. This raises the possibility that at least one of the major components of chronic airway damage in asthma, epithelial shedding and denudation, may in part result from a major therapy for the disease.
authors.affiliation: McDonald Research Laboratories, the iCAPTURE Centre, University of British Columbia, Vancouver, British Columbia, Canada. ddorscheid@mrl.ubc.ca
authors.forename: D R
authors.initials: DR
authors.lastname: Dorscheid
authors.forename: K R
authors.initials: KR
authors.lastname: Wojcik
authors.forename: S
authors.initials: S
authors.lastname: Sun
authors.forename: B
authors.initials: B
authors.lastname: Marroquin
authors.forename: S R
authors.initials: SR
authors.lastname: White
mesh_terms: D018927:Anti-Asthmatic Agents / Q000009:adverse effects*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D001507:Beclomethasone / Q000009:adverse effects*; D001993:Bronchodilator Agents / Q000009:adverse effects*; D019819:Budesonide / Q000009:adverse effects*; D053453:Caspase 9; D020169:Caspases / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects; D002908:Chronic Disease; D003574:Cytochrome c Group / Q000187:drug effects / Q000502:physiology; D003907:Dexamethasone / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019254:Genes, bcl-2 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology; D015375:Receptors, Interleukin-2 / Q000187:drug effects* / Q000502:physiology; D020545:Respiratory Mucosa / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D014221:Triamcinolone / Q000009:adverse effects*; D051020:bcl-X Protein; D019014:fas Receptor
chemical_list: D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; C494811:BCL2L1 protein, human; D001993:Bronchodilator Agents; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2; D051020:bcl-X Protein; D019014:fas Receptor; D014221:Triamcinolone; D019819:Budesonide; D003907:Dexamethasone; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D001507:Beclomethasone