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. 2013 Oct 4;14(1):98.
doi: 10.1186/1465-9921-14-98.

Budesonide and formoterol effects on rhinovirus replication and epithelial cell cytokine responses

Yury A Bochkov, 威廉·W总线se, Rebecca A Brockman-Schneider, Michael D Evans, Nizar N Jarjour, Christopher McCrae, Anna Miller-Larsson, James E Gern
Free PMC article

Budesonide and formoterol effects on rhinovirus replication and epithelial cell cytokine responses

Yury A Bochkovet al. Respir Res. .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Viral replication in BE cells from normal and asthmatic subjects was not affected by budesonide or formoterol.Cells were inoculated with RV-16 after 24 h pre-treatment with budesonide (B), formoterol (F), both drugs (B+F), or media alone (none) and cell-associated viral RNA was measured 24 h post-inoculation. Neither B, F, nor the combination significantly affected RV replication in all samples( A ), nor in samples grouped according to asthma status( B ). Data are represented as geometric means with 95% confidence intervals.
Figure 2
Figure 2
Effects of RV infection and drug treatments on cytokine protein secretion by BE cells from normal and asthmatic subjects.Cells were inoculated with RV-16 after 24 h pre-treatment with budesonide (B), formoterol (F), the combination (B+F) or media alone (none), and samples of tissue culture medium obtained 24 h post inoculation were tested for cytokines. Data are represented as geometric (CXCL10, TNFα) or arithmetic (CXCL8) means with 95% confidence intervals.
Figure 3
Figure 3
Treatment effects on expression of interferon mRNA by BE cells from normal and asthmatic subjects.Cells were inoculated with RV-16 after 24 h pre-treatment with budesonide (B), formoterol (F), the combination (B+F) or media alone (none) and then type I (IFNB1) and III (IL28) interferon mRNA levels were measured by qPCR in cell lysates 24 h post inoculation. Data are represented as geometric mean fold change compared to mock-infected cells with 95% confidence intervals.
Figure 4
Figure 4
Correlations between RV RNA levels and cytokine responses in BE cells.RV RNA 24 h after inoculation was positively associated with IFNB1 mRNA( A ), IL28 mRNA( B ), and CXCL10 cytokine secretion( C )and mRNA upregulation( D ). Samples include untreated samples and also those treated with budesonide, formoterol, and the combination. Results from samples in the normal and asthma groups are indicated by squares and circles, respectively, and separate regression lines (solid line, normal; dotted line, asthma) are plotted for each group.
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