Effects of inflammation and acute beta-agonist inhalation on beta 2-AR signaling in human airways.
Although alterations in beta 2-adrenergic receptor (AR) responsiveness may in part explain reports linking deterioration of asthma control with beta-agonist treatment of asthmatics, few data exist on beta 2-AR regulation in human airway cells. We have employed a bronchoscopy model to examine inflammation- and beta-agonist-induced alterations in human bronchial epithelial cell beta 2-AR density and responsiveness. Allergic asthmatic subjects participated in 2-day protocols examining airways before and 24 h after segmental antigen challenge (SAC) with ragweed. To assess the effect of acute beta-agonist exposure, bronchoscopies were performed both with (+ beta-Ag) and without (-beta-Ag) inhalation of beta-agonist 30 min before the procedure. Measurements of inflammatory cell infiltration were obtained by analysis of bronchoalveolar lavage fluid, and beta 2-AR density and responsiveness were examined in bronchial epithelial cells obtained by bronchoscopic brushing. Neither SAC nor acute beta-agonist administration alone significantly affected epithelial cell beta 2-AR density. beta-Agonist-stimulated adenosine 3', 5'-cyclic monophosphate (cAMP) generation was significantly lower in the + beta-Ag groups compared with the-beta-Ag group, demonstrating acute agonist-specific beta 2-AR desensitization in vivo. SAC caused a small, statistically insignificant reduction in beta-Agonist-stimulated cAMP production in both -beta-Ag or + beta-Ag groups. These lata suggest that acute beta-agonist inhalation, but not airway inflammation, significantly reduces maximal beta 2-AR responsiveness in airway cells.
Department of Pharmacology, Jefferson Cancer Institute, Philadelphia, Pennsylvania 19107, USA.
R B
RB
Penn
J R
JR
Shaver
J G
JG
Zangrilli
M
M
Pollice
J E
JE
Fish
S P
SP
Peters
J L
JL
Benovic
D000420:Albuterol / Q000494:pharmacology; D000485:Allergens; D001980:Bronchi / Q000166:cytology; D001992:Bronchoalveolar Lavage Fluid; D000242:Cyclic AMP / Q000378:metabolism; D015536:Down-Regulation; D004848:Epithelium / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000503:physiopathology*; D066298:In Vitro Techniques; D016210:Methacholine Chloride; D010869:Pindolol / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D015398:Signal Transduction
D000485:Allergens; D018343:Receptors, Adrenergic, beta-2; D016210:Methacholine Chloride; D010869:Pindolol; D000242:Cyclic AMP; D000420:Albuterol