Airway mucosal thickening and bronchial hyperresponsiveness induced by inhaled beta 2-agonist in mice.
BACKGROUND
Patients with chronic persistent asthma require frequent use of inhaled beta(2)-agonist, which may result in aggravation of asthma symptoms. Our recent in vitro study has shown that beta(2)-agonist stimulates the growth of human airway epithelial cell lines.


OBJECTIVE
To determine whether beta(2)-agonist likewise affects airway epithelial cell proliferation in vivo and, if so, what the mechanism of action is, we examined the effect of salbutamol on the morphology of murine airways.


METHODS
Seventy-two BALB/c mice were administered aerosolized salbutamol using "flow-through" nose-only inhalation chambers at daily doses of 0.2 to 20 microg for up to 6 weeks. Morphology of tracheal mucosa, labeling of epithelial cells with 5-bromo-2'-deoxyuridine (BrdU), and bronchial responsiveness were assessed.


RESULTS
Exposure to salbutamol increased the thickness of tracheal epithelial layer and the number of BrdU-positive epithelial cells in a dose- and time-dependent manner: the values in mice receiving 20 microg salbutamol for 6 weeks were 247% and 642%, respectively, of those in control animals receiving saline solution alone. These effects were inhibited by the mitogen-activated protein (MAP) kinase kinase inhibitors PD98059 and U0126. Salbutamol also caused a decrease in the provocative concentration of methacholine to achieve 400% of baseline enhanced pause. Combined treatment with inhaled budesonide attenuated salbutamol-induced airway morphologic changes and bronchial hyperresponsiveness.


CONCLUSIONS
beta(2)-agonist stimulates proliferation of airway epithelial cells and produces airway wall thickening in vivo via MAP kinase-dependent pathway, and these effects are prevented by inhaled corticosteroid.
Tamaoki
Jun
J
First Department of Medicine, Tokyo Women's Medical University School of Medicine, Japan. jtamaoki@chi.twmu.ac.jp
Tagaya
Etsuko
E
Kawatani
Kiyomi
K
Nakata
Junko
J
Endo
Yumie
Y
Nagai
Atsushi
A
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000633:toxicity*; D000420:Albuterol / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000473:pathology; D014132:Trachea / Q000187:drug effects* / Q000473:pathology
D000318:Adrenergic beta-Agonists; D000420:Albuterol