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Chronic β2AR stimulation limits CFTR activation in human airway epithelia
John J. Brewington, … , L. Jason Lu, John P. Clancy
John J. Brewington, … , L. Jason Lu, John P. Clancy
Published February 22, 2018
Citation Information: JCI Insight. 2018;3(4):e93029. https://doi.org/10.1172/jci.insight.93029.
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Research Article Cell biology Pulmonology

Chronic β2AR stimulation limits CFTR activation in human airway epithelia

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Abstract

Traditional pulmonary therapies for cystic fibrosis (CF) target the downstream effects of CF transmembrane conductance regulator (CFTR) dysfunction (the cause of CF). Use of one such therapy, β-adrenergic bronchodilators (such as albuterol), is nearly universal for airway clearance. Conversely, novel modulator therapies restore function to select mutant CFTR proteins, offering a disease-modifying treatment. Recent trials of modulators targeting F508del-CFTR, the most common CFTR mutation, suggest that chronic β-agonist use may undermine clinical modulator benefits. We therefore sought to understand the impact of chronic or excess β-agonist exposure on CFTR activation in human airway epithelium. The present studies demonstrate a greater than 60% reduction in both wild-type and modulator-corrected F508del-CFTR activation following chronic exposure to short- and long-acting β-agonists. This reduction was due to reduced cellular generation of cAMP downstream of the β-2 adrenergic receptor–G protein complex. Our results point towards a posttranscriptional reduction in adenylyl cyclase function as the mechanism of impaired CFTR activation produced by prolonged β-agonist exposure. β-Agonist–induced CFTR dysfunction was sufficient to abrogate VX809/VX770 modulation of F508del-CFTR in vitro. Understanding the clinical relevance of our observations is critical for CF patients using these drugs, and for investigators to inform future CFTR modulator drug trials.

Authors

John J. Brewington, Jessica Backstrom, Amanda Feldman, Elizabeth L. Kramer, Jessica D. Moncivaiz, Alicia J. Ostmann, Xiaoting Zhu, L. Jason Lu, John P. Clancy

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Figure 7

Chronic albuterol exposure reduces forskolin/IBMX–stimulated generation of cAMP in wtCFTR+ and F508del-CFTR+ CFBE41o- cells.

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Chronic albuterol exposure reduces forskolin/IBMX–stimulated generation ...
wtCFTR+ and F508del-CFTR+ CFBE41o- cells were pretreated with albuterol (10 μM) for 72 hours, then stimulated to produce cAMP with 10 μM forskolin/100 μM IBMX (10 minutes). cAMP levels were then analyzed by colorimetric ELISA. wtCFTR+ (A, n = 6) and F508del-CFTR+ (B, n = 6) CFBE41o- cells produce minimal cAMP in the absence of either pretreatment or stimulation (open circles). Stimulation with 10 μM forskolin/100 μM IBMX in untreated cells leads to cAMP production (open squares), which is reduced by more than 60% in cells pretreated for 72 hours with albuterol (open triangles). All studies are internally normalized to control conditions to allow for comparisons. Both experiments are representative of studies repeated in duplicate with similar results. Data presented represent the mean ± SEM. n = 6 wells per condition. ****P < 0.0005 by 1-way ANOVA with Tukey’s multiple comparisons test.

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