چکیده (انگلیسی):

Background: Inhaled corticosteroids enhance airway epithelial barrier integrity. However, the mechanism
by which they accomplish this is unclear. Therefore, we investigated steroid-inducible genes and
signaling pathways that were involved in enhancing airway epithelial barrier integrity.
Methods: A human bronchial epithelial cell line (16HBE cells) was cultured with 10
6 M dexamethasone
(DEX) for 3 days to enhance epithelial barrier integrity. After measuring transepithelial electrical resistance
(TER) and paracellular permeability, we extracted total RNA from 16HBE cells and performed
microarray and pathway analysis. After we identified candidate genes and a canonical pathway, we
measured TER and immunostained for tight junction (TJ) and adherent junction (AJ) proteins in cells that
had been transfected with specific small interfering RNAs (siRNAs) for these genes.
Results: We identified a nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated oxidative stress
response pathway which was primarily involved in the steroid-induced enhancement of airway
epithelial barrier integrity. Transfecting cells with Nrf2 specific siRNA reduced the steroid-induced
enhancement of airway epithelial barrier integrity and the accumulation of TJ and AJ proteins at sites
of cellecell contact. Moreover, based on pathway analysis, aldehyde oxidase 1 (AOX1) was identified as a
downstream enzyme of Nrf2. Transfecting cells with AOX1-specific siRNA also reduced the steroidinduced
enhancement of airway epithelial barrier integrity.
Conclusions: Our results indicated that the Nrf2/AOX1 pathway was important for enhancing airway
epithelial barrier integrity. Because the airway epithelium of asthmatics is susceptible to reduced barrier
integrity, this pathway might be a new therapeutic target for asthma.