Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion

Takefumi Mizutani, Masahiro Morise, Yasushi Ito, Yoshitaka Hibino, Tadakatsu Matsuno, Satoru Ito, Naozumi Hashimoto, Mitsuo Sato, Masashi Kondo, Kazuyoshi Imaizumi, Yoshinori Hasegawa

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

This study investigated the physiological effects of inhaled corticosteroids, which are used widely to treat asthma. The application of fluticasone propionate (FP, 100 μM) induced sustained increases in the short-circuit current (ISC) in human airway Calu-3 epithelial cells. The FP-induced ISC was prevented by the presence of H89 (10 μM, a protein kinase A inhibitor) and SQ22536 (100 μM, an adenylate cyclase inhibitor). The FP-induced responses involved bumetanide (a Na +-K+-2Cl- cotransporter inhibitor)-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid (an inhibitor of HCO3 2-dependent anion transporters)-sensitive components, both of which reflect basolateral anion transport. Further, FP augmented apical membrane Cl - current (ICl), reflecting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance, in the nystatin-permeabilized monolayer. In ISC and ICl responses, FP failed to enhance the responses to forskolin (10 μM, an adenylate cyclase activator). Nevertheless, we found that FP synergistically increased cytosolic cAMP concentrations in combination with forskolin. All these effects of FP were reproduced with the use of budesonide. Collectively, inhaled corticosteroids such as FP and budesonide stimulate CFTR-mediated anion transport through adenylate cyclase-mediated mechanisms in a nongenomic fashion, thus sharing elements of a common pathway with forskolin. However, the corticosteroids cooperate with forskolin for synergistic cAMPproduction, suggesting that the corticosteroids and forskolin do not compete with each other to exert their effects on adenylate cyclase. Considering that such synergism was also observed in the FP/salmeterol combination, these nongenomic aspects may play therapeutic roles in mucus congestive airway diseases, in addition to genomic aspects that are generally recognized.

Original languageEnglish
Pages (from-to)645-651
Number of pages7
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume47
Issue number5
DOIs
Publication statusPublished - 01-11-2012

Fingerprint

Budesonide
Colforsin
Anions
Adenylyl Cyclases
Adrenal Cortex Hormones
Short circuit currents
Cystic Fibrosis Transmembrane Conductance Regulator
Bumetanide
Nystatin
Mucus
Protein Kinase Inhibitors
Cyclic AMP-Dependent Protein Kinases
Monolayers
Asthma
Epithelial Cells
Fluticasone
Membranes
Acids

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Mizutani, Takefumi ; Morise, Masahiro ; Ito, Yasushi ; Hibino, Yoshitaka ; Matsuno, Tadakatsu ; Ito, Satoru ; Hashimoto, Naozumi ; Sato, Mitsuo ; Kondo, Masashi ; Imaizumi, Kazuyoshi ; Hasegawa, Yoshinori. / Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion. In: American Journal of Respiratory Cell and Molecular Biology. 2012 ; Vol. 47, No. 5. pp. 645-651.
@article{3b5194698ccf4984b9e37a41e71c905d,
title = "Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion",
abstract = "This study investigated the physiological effects of inhaled corticosteroids, which are used widely to treat asthma. The application of fluticasone propionate (FP, 100 μM) induced sustained increases in the short-circuit current (ISC) in human airway Calu-3 epithelial cells. The FP-induced ISC was prevented by the presence of H89 (10 μM, a protein kinase A inhibitor) and SQ22536 (100 μM, an adenylate cyclase inhibitor). The FP-induced responses involved bumetanide (a Na +-K+-2Cl- cotransporter inhibitor)-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid (an inhibitor of HCO3 2-dependent anion transporters)-sensitive components, both of which reflect basolateral anion transport. Further, FP augmented apical membrane Cl - current (ICl), reflecting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance, in the nystatin-permeabilized monolayer. In ISC and ICl responses, FP failed to enhance the responses to forskolin (10 μM, an adenylate cyclase activator). Nevertheless, we found that FP synergistically increased cytosolic cAMP concentrations in combination with forskolin. All these effects of FP were reproduced with the use of budesonide. Collectively, inhaled corticosteroids such as FP and budesonide stimulate CFTR-mediated anion transport through adenylate cyclase-mediated mechanisms in a nongenomic fashion, thus sharing elements of a common pathway with forskolin. However, the corticosteroids cooperate with forskolin for synergistic cAMPproduction, suggesting that the corticosteroids and forskolin do not compete with each other to exert their effects on adenylate cyclase. Considering that such synergism was also observed in the FP/salmeterol combination, these nongenomic aspects may play therapeutic roles in mucus congestive airway diseases, in addition to genomic aspects that are generally recognized.",
author = "Takefumi Mizutani and Masahiro Morise and Yasushi Ito and Yoshitaka Hibino and Tadakatsu Matsuno and Satoru Ito and Naozumi Hashimoto and Mitsuo Sato and Masashi Kondo and Kazuyoshi Imaizumi and Yoshinori Hasegawa",
year = "2012",
month = "11",
day = "1",
doi = "10.1165/rcmb.2012-0076OC",
language = "English",
volume = "47",
pages = "645--651",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "5",

}

Mizutani, T, Morise, M, Ito, Y, Hibino, Y, Matsuno, T, Ito, S, Hashimoto, N, Sato, M, Kondo, M, Imaizumi, K & Hasegawa, Y 2012, 'Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion', American Journal of Respiratory Cell and Molecular Biology, vol. 47, no. 5, pp. 645-651. https://doi.org/10.1165/rcmb.2012-0076OC

Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion. / Mizutani, Takefumi; Morise, Masahiro; Ito, Yasushi; Hibino, Yoshitaka; Matsuno, Tadakatsu; Ito, Satoru; Hashimoto, Naozumi; Sato, Mitsuo; Kondo, Masashi; Imaizumi, Kazuyoshi; Hasegawa, Yoshinori.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 47, No. 5, 01.11.2012, p. 645-651.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion

AU - Mizutani, Takefumi

AU - Morise, Masahiro

AU - Ito, Yasushi

AU - Hibino, Yoshitaka

AU - Matsuno, Tadakatsu

AU - Ito, Satoru

AU - Hashimoto, Naozumi

AU - Sato, Mitsuo

AU - Kondo, Masashi

AU - Imaizumi, Kazuyoshi

AU - Hasegawa, Yoshinori

PY - 2012/11/1

Y1 - 2012/11/1

N2 - This study investigated the physiological effects of inhaled corticosteroids, which are used widely to treat asthma. The application of fluticasone propionate (FP, 100 μM) induced sustained increases in the short-circuit current (ISC) in human airway Calu-3 epithelial cells. The FP-induced ISC was prevented by the presence of H89 (10 μM, a protein kinase A inhibitor) and SQ22536 (100 μM, an adenylate cyclase inhibitor). The FP-induced responses involved bumetanide (a Na +-K+-2Cl- cotransporter inhibitor)-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid (an inhibitor of HCO3 2-dependent anion transporters)-sensitive components, both of which reflect basolateral anion transport. Further, FP augmented apical membrane Cl - current (ICl), reflecting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance, in the nystatin-permeabilized monolayer. In ISC and ICl responses, FP failed to enhance the responses to forskolin (10 μM, an adenylate cyclase activator). Nevertheless, we found that FP synergistically increased cytosolic cAMP concentrations in combination with forskolin. All these effects of FP were reproduced with the use of budesonide. Collectively, inhaled corticosteroids such as FP and budesonide stimulate CFTR-mediated anion transport through adenylate cyclase-mediated mechanisms in a nongenomic fashion, thus sharing elements of a common pathway with forskolin. However, the corticosteroids cooperate with forskolin for synergistic cAMPproduction, suggesting that the corticosteroids and forskolin do not compete with each other to exert their effects on adenylate cyclase. Considering that such synergism was also observed in the FP/salmeterol combination, these nongenomic aspects may play therapeutic roles in mucus congestive airway diseases, in addition to genomic aspects that are generally recognized.

AB - This study investigated the physiological effects of inhaled corticosteroids, which are used widely to treat asthma. The application of fluticasone propionate (FP, 100 μM) induced sustained increases in the short-circuit current (ISC) in human airway Calu-3 epithelial cells. The FP-induced ISC was prevented by the presence of H89 (10 μM, a protein kinase A inhibitor) and SQ22536 (100 μM, an adenylate cyclase inhibitor). The FP-induced responses involved bumetanide (a Na +-K+-2Cl- cotransporter inhibitor)-sensitive and 4,4'-dinitrostilbene-2,2'-disulfonic acid (an inhibitor of HCO3 2-dependent anion transporters)-sensitive components, both of which reflect basolateral anion transport. Further, FP augmented apical membrane Cl - current (ICl), reflecting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance, in the nystatin-permeabilized monolayer. In ISC and ICl responses, FP failed to enhance the responses to forskolin (10 μM, an adenylate cyclase activator). Nevertheless, we found that FP synergistically increased cytosolic cAMP concentrations in combination with forskolin. All these effects of FP were reproduced with the use of budesonide. Collectively, inhaled corticosteroids such as FP and budesonide stimulate CFTR-mediated anion transport through adenylate cyclase-mediated mechanisms in a nongenomic fashion, thus sharing elements of a common pathway with forskolin. However, the corticosteroids cooperate with forskolin for synergistic cAMPproduction, suggesting that the corticosteroids and forskolin do not compete with each other to exert their effects on adenylate cyclase. Considering that such synergism was also observed in the FP/salmeterol combination, these nongenomic aspects may play therapeutic roles in mucus congestive airway diseases, in addition to genomic aspects that are generally recognized.

UR - http://www.scopus.com/inward/record.url?scp=84868314597&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84868314597&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2012-0076OC

DO - 10.1165/rcmb.2012-0076OC

M3 - Article

C2 - 22798431

AN - SCOPUS:84868314597

VL - 47

SP - 645

EP - 651

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 5

ER -