Steroids completely reverse albuterol-induced β₂-adrenergic receptor tolerance in human small airways

Concentration responses to carbachol (CCh) and isoproterenol (ISO) inducing airway luminal area narrowing and increasing airway luminal area. A, A typical contraction of a human small airway to carbachol and a mean concentration-response curve. B, The same airway as shown in panel A, relaxing to increasing concentrations of isoproterenol. The mean concentration-response curve is also shown. Data are expressed as means ± SEMs. Each group contains 2 airways from each of the 5 donors (10 total airways).

Chronic exposure to albuterol induces β₂-AR desensitization in a dose- and time-dependent manner. Concentration-response curves to isoproterenol (ISO; 10⁻⁹ to 10⁻⁴ mol/L) after the incubation of albuterol (1.0, 0.1, or 0.01 μmol/L) after 3 (A), 6 (B), or 12 (C) hours with lung slices containing human small airways are shown. Solid squares, Control; solid circles, 0.01 μmol/L albuterol; open squares, 0.1 μmol/L albuterol; open circles, 1.0 μmol/L albuterol. D, Table of mean EC₅₀ and E_max values of isoproterenol were calculated from airways. Each group contains 2 airways from each of the 4 donors (8 total airways).

β₂-AR desensitization occurs upstream of adenylyl cyclase activation. Concentration responses to forskolin (10⁻⁸ to 10⁻⁴ mol/L) on human small airways after incubation with albuterol for 12 hours at a concentration of 1.0 μmol/L versus control airway values is shown. Solid squares, Control; open squares, albuterol (1.0 μmol/L; 12 hours). Each group contains 4 airways from each of the 2 donors (8 total airways).

Steroids prevent β-agonist–induced β₂-AR desensitization. A, Concentration-response curves to isoproterenol (ISO; 10⁻⁹ to 10⁻⁴ mol/L). B, Log EC₅₀ values of isoproterenol were calculated from airways. ^∗P < .05 and ^∗∗ P < .01 versus the control group or ###P < .001 versus the albuterol group. Solid squares, Control; open circles, 1.0 μmol/L dexamethasone (Dex); open triangles, 0.1 μmol/L albuterol (Alb); open squares, 1.0 μmol/L dexamethasone plus 0.1 μmol/L albuterol. Each group contains 2 airways from each of the 4 donors (8 total airways).

Effects of albuterol (Alb) and dexamethasone (Dex) on β₂-AR expression. Lung slices were homogenized, and quantitative radioligand binding with iodine 125–labeled cyanopindolol was carried out, as described in the Methods section. ^∗P = .013 versus the untreated control group. Solid squares, Control; open circles, 1.0 μmol/L dexamethasone; open triangles, 0.1 μmol/L albuterol; open squares, 1.0 μmol/L dexamethasone plus 0.1 μmol/L albuterol. Each group contains 5 airways from each of the 5 donors (25 total airways).