Budesonide enhances agonist-induced bronchodilation in human small airways by increasing cAMP production in airway smooth muscle
| Autor: | Maia L. Corpuz, Cynthia J. Koziol-White, Timothy B. Johnstone, I.A. Dainty, Vishal Parikh, Reynold A. Panettieri, Brian Deeney, Gaoyuan Cao, Omar Tliba, Rennolds S. Ostrom, Sarah Orfanos |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine Agonist Budesonide Cholera Toxin Myosin Light Chains Physiology medicine.drug_class Camp production Bronchi Pharmacology Dinoprostone 03 medical and health sciences 0302 clinical medicine Receptors Glucocorticoid Physiology (medical) Formoterol Fumarate Bronchodilation medicine Cyclic AMP Humans Phosphorylation Beneficial effects Asthma business.industry Small airways Cell Membrane Colforsin Muscle Smooth Cell Biology Airway smooth muscle medicine.disease Bronchodilator Agents 030104 developmental biology 030220 oncology & carcinogenesis Fluticasone Prednisone Carbachol business medicine.drug Research Article |
| Zdroj: | Am J Physiol Lung Cell Mol Physiol |
| ISSN: | 1522-1504 |
| Popis: | The nongenomic mechanisms by which glucocorticoids modulate β2 agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision-cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2), cholera toxin (CTX), or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2, or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone, and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2, CTX, or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation and that potentially mediated the rapid effects of steroids on β2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor-α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol-induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and β2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease. |
| Databáze: | OpenAIRE |
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