Steroids completely reverse albuterol-induced β2-adrenergic receptor tolerance in human small airways Philip R. Cooper, PhD, Reynold A. Panettieri, MD

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Presentation transcript:

Steroids completely reverse albuterol-induced β2-adrenergic receptor tolerance in human small airways Philip R. Cooper, PhD, Reynold A. Panettieri, MD Journal of Allergy and Clinical Immunology Volume 122, Issue 4, Pages 734-740 (October 2008) DOI: 10.1016/j.jaci.2008.07.040 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 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). Journal of Allergy and Clinical Immunology 2008 122, 734-740DOI: (10.1016/j.jaci.2008.07.040) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 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 Emax values of isoproterenol were calculated from airways. Each group contains 2 airways from each of the 4 donors (8 total airways). Journal of Allergy and Clinical Immunology 2008 122, 734-740DOI: (10.1016/j.jaci.2008.07.040) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 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). Journal of Allergy and Clinical Immunology 2008 122, 734-740DOI: (10.1016/j.jaci.2008.07.040) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 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). Journal of Allergy and Clinical Immunology 2008 122, 734-740DOI: (10.1016/j.jaci.2008.07.040) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 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). Journal of Allergy and Clinical Immunology 2008 122, 734-740DOI: (10.1016/j.jaci.2008.07.040) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions