Long-acting Beta2-adrenergic Agonist and Inhaled Corticosteroids for Asthma Induced Mucus Production With Human Airway Basal Cells In Vitro ALI Model

Abstract RATIONALE: In the treatment strategy for asthma, the use of inhaled drugs is the first choice. Current guidelines focus on clinical symptomatic effects, but less is known about the effects on the airway epithelium of inhaled drugs that act on bronchial smooth muscle and exert their bronchodilator effects. In the present study, we used a bronchial asthma model In Vitro to investigate the effects on the airway epithelium of inhaled drugs that exert bronchodilator effects via the airway epithelium.METHODS: To assess the effects of inhaled Drugs, Long-Acting Beta2-adrenergic Agonist (LABA) and Inhaled Corticosteroids (ICS) in regulating differentiation of the human airway epithelium with bronchial asthma model induced by Interleukin (IL)-13, primary human airway basal stem/progenitor cells (BC) from nonsmokers were cultured on air-liquid interface (ALI) cultures to mimic the airway epithelium in vitro. Those specimens were analyzed by pathological and molecular biological methods, and by scanning electron microscopy (SEM) to study the effects of inhaled drugs on bronchial asthma models.RESULTS: Normal differentiation of mucus and ciliated cells was observed on day 14 in ALI culture of human airway BCs; increased mucus cells and decreased ciliated cells were observed in the bronchial asthma model created by addition of IL-13. The addition of inhaled drugs, especially LABA, showed increased production of viscous mucin on the cell surface. Pathological findings showed a further increase in mucus cells and a significant increase in mucus cells (MUC5AC) at the gene expression (LABA 6.9 times, p<0.0001; ICS 2.7 times. p>0.01) and protein level by western blot analysis (LABA 1.2 times, p<0.0001; ICS 1.0 times p<0.05) compared to control. In ciliated cell, LABA tended to recover cilia expression (about 1.2 times), but ICS had no significant difference to recover cilia. SEM showed that the ciliated cells in the inhaled LABA and/or ICS recovered better than those in control.CONCLUSIONS: Inhaled drugs for bronchial asthma, LABA and ICS induced more mucus production than naïve and control in airway epithelium. Therefore, both LABAs and ICSs, despite their dilating on tracheobronchial smooth muscle and anti-inflammatory effects, may have adverse effects on the airway epithelium and require some therapeutic intervention.