Budesonide and formoterol effects on rhinovirus replication and epithelial cell cytokine responses.
BACKGROUND
Combination therapy with budesonide and formoterol reduces exacerbations of asthma, which are closely associated with human rhinovirus (RV) infections in both children and adults. These data suggest that budesonide and formoterol inhibit virus-induced inflammatory responses of airway epithelial cells.


METHODS
To test this hypothesis, bronchial epithelial (BE) cells were obtained from airway brushings of 8 subjects with moderate-to-severe allergic asthma and 9 with neither asthma nor respiratory allergies. Cultured BE cells were incubated for 24 hours with budesonide (1.77 µM), formoterol (0.1 µM), both, or neither, and then inoculated with RV-16 (5×10(6) plaque forming units [PFU]/mL). After 24 hours, viral replication (RV RNA), cytokine secretion (CXCL8, CXCL10, TNFa, IFN-ß, IL-28) and mRNA expression (CXCL8, CXCL10, TNF, IFNB1, IL-28) were analyzed.


RESULTS
RV infection induced CXCL10 protein secretion and IFNB1 and IL28 mRNA expression. Drug treatments significantly inhibited secretion of CXCL10 in mock-infected, but not RV-infected, BE cells, and inhibited secretion of TNFa under both conditions. Neither budesonide nor formoterol, alone or in combination, significantly affected viral replication, nor did they inhibit RV-induced upregulation of IFNB1 and IL28 mRNA. Overall, RV replication was positively related to CXCL10 secretion and induction of IFNB1 and IL28 mRNA, but the positive relationship between RV RNA and CXCL10 secretion was stronger in normal subjects than in subjects with asthma.


CONCLUSIONS
Budesonide and formoterol can inhibit BE cell inflammatory responses in vitro without interfering with viral replication or production of interferons. These effects could potentially contribute to beneficial effects of budesonide/formoterol combination therapy in preventing RV-induced asthma exacerbations.
Yury A
YA
Bochkov
William W
WW
Busse
Rebecca A
RA
Brockman-Schneider
Michael D
MD
Evans
Nizar N
NN
Jarjour
Christopher
C
McCrae
Anna
A
Miller-Larsson
James E
JE
Gern
D000328:Adult; D001249:Asthma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D001993:Bronchodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019819:Budesonide / Q000494:pharmacology* / Q000627:therapeutic use; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004359:Drug Therapy, Combination; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D004983:Ethanolamines / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010850:Picornaviridae Infections / Q000150:complications; D012229:Rhinovirus / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
D001993:Bronchodilator Agents; D054357:Chemokine CXCL10; D016207:Cytokines; D004983:Ethanolamines; D014409:Tumor Necrosis Factor-alpha; D019819:Budesonide; D000068759:Formoterol Fumarate