Estrogen replacement therapy prevents airway dysfunction in a murine model of allergen-induced asthma.
We previously reported that 17beta-estradiol (E2) prevents hyperresponsiveness to carbachol of murine asthmatic tracheal rings in vitro. We now investigated whether E2 is similarly effective in reducing airway hyperreactivity in a murine model of allergic asthma in vivo. Female ovariectomized BALB/c mice were rendered asthmatic by a 25-day protocol of sensitization to ovalbumin. Under positive-pressure ventilation, anesthetized asthmatic mice exhibited a dramatic increase in airway responsiveness to increasing doses of inhaled methacholine compared to PBS-sensitized controls, as reflected in decreased dynamic compliance of the respiratory system and increased tissue damping, tissue elastance, and airway resistance. Furthermore, asthmatic mice exhibited hypercellularity and increased protein concentration in the bronchoalveolar lavage, strong signs of peribronchial cuffing with inflammatory cells and increased goblet cell activity. To test the effects of estrogen, three additional groups of mice were implanted subcutaneously with different amounts of slow-release E2 pellets at the time of ovariectomy and rendered asthmatic as before. E2 dose-dependently inhibited airway hyperresponsiveness to methacholine, reduced bronchoalveolar lavage hypercellularity, and virtually eliminated histologic signs of inflammation and goblet cell hyperactivity. The inflammation and airway hyperactivity in asthmatic mice was associated with an increase in bronchoalveolar lavage levels of TGFbeta1, which was completely abolished in E2-treated asthmatic mice. We conclude that estrogen replacement therapy effectively ameliorates the pathologic profile of murine allergic asthma.
Dimitropoulou
Christiana
C
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia, 30912-2300, USA. cdimitro@mcg.edu
Drakopanagiotakis
Fotios
F
Chatterjee
Anuran
A
Snead
Connie
C
Catravas
John D
JD
D000485:Allergens; D000818:Animals; D000906:Antibodies / Q000097:blood; D001249:Asthma / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage* / Q000097:blood; D015914:Estrogen Replacement Therapy; D005260:Female; D020397:Goblet Cells / Q000187:drug effects* / Q000276:immunology; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D010052:Ovariectomy; D015656:Respiratory Mechanics / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D000485:Allergens; D000906:Antibodies; D016085:Bronchoconstrictor Agents; D004343:Drug Implants; D053773:Transforming Growth Factor beta1; D016210:Methacholine Chloride; D004958:Estradiol; D010047:Ovalbumin