Nongenomic effects of fluticasone propionate and budesonide on human airway anion secretion.
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 (I(SC)) in human airway Calu-3 epithelial cells. The FP-induced I(SC) 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 HCO(3)(-)-dependent anion transporters)-sensitive components, both of which reflect basolateral anion transport. Further, FP augmented apical membrane Cl(-) current (I(Cl)), reflecting cystic fibrosis transmembrane conductance regulator (CFTR)-mediated conductance, in the nystatin-permeabilized monolayer. In I(SC) and I(Cl) 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 cAMP production, 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.
Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Takefumi
T
Mizutani
Masahiro
M
Morise
Yasushi
Y
Ito
Yoshitaka
Y
Hibino
Tadakatsu
T
Matsuno
Satoru
S
Ito
Naozumi
N
Hashimoto
Mitsuo
M
Sato
Masashi
M
Kondo
Kazuyoshi
K
Imaizumi
Yoshinori
Y
Hasegawa
D000280:Administration, Inhalation; D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000494:pharmacology*; D000730:Androstadienes / Q000008:administration & dosage* / Q000494:pharmacology; D027321:Anion Transport Proteins / Q000378:metabolism; D019819:Budesonide / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D000068298:Fluticasone; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D020545:Respiratory Mucosa / Q000166:cytology*; D015290:Second Messenger Systems / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D000730:Androstadienes; D027321:Anion Transport Proteins; D002712:Chlorides; D005576:Colforsin; D019819:Budesonide; D000068298:Fluticasone; D000242:Cyclic AMP