Dataset Information

Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.

ABSTRACT:

Background and purpose

Statin treatment may ameliorate viral infection-induced exacerbations of chronic obstructive pulmonary disease (COPD), which exhibit Th2-type bronchial inflammation. Thymic stromal lymphopoietin (TSLP), a hub cytokine switching on Th2 inflammation, is overproduced in viral and dsRNA-stimulated bronchial epithelial cells from COPD donors. Hence, TSLP may be causally involved in exacerbations. This study tests the hypothesis that simvastatin inhibits dsRNA-induced TSLP.

Experimental approach

Epithelial cells, obtained by bronchoscopy from COPD (n = 7) and smoker control (n = 8) donors, were grown and stimulated with a viral infection and danger signal surrogate, dsRNA (10??g·mL(-1) ). Cells were treated with simvastatin (0.2-5??g·mL(-1) ), with or without mevalonate (13-26??g·mL(-1) ), or dexamethasone (1??g·mL(-1) ) before dsRNA. Cytokine expression and production, and transcription factor (IRF3 and NF-?B) activation were determined.

Key results

dsRNA induced TSLP, TNF-?, CXCL8 and IFN-?. TSLP was overproduced in dsRNA-exposed COPD cells compared with control. Simvastatin, but not dexamethasone, concentration-dependently inhibited dsRNA-induced TSLP. Unexpectedly, simvastatin acted independently of mevalonate and did not affect dsRNA-induced NF-?B activation nor did it reduce production of TNF-? and CXCL8. Instead, simvastatin inhibited dsRNA-induced IRF3 phosphorylation and generation of IFN-?.

Conclusions and implications

Independent of mevalonate and NF-?B, previously acknowledged anti-inflammatory mechanisms of pleiotropic statins, simvastatin selectively inhibited dsRNA-induced IRF3 activation and production of TSLP and IFN-? in COPD epithelium. These data provide novel insight into epithelial generation of TSLP and suggest paths to be exploited in drug discovery aimed at inhibiting TSLP-induced pulmonary immunopathology.

SUBMITTER: Brandelius A

PROVIDER: S-EPMC3572563 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Publications

Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.

Brandelius Angelica A Mahmutovic Persson Irma I Calvén Jenny J Bjermer Leif L Persson Carl G A CG Andersson Morgan M Uller Lena L

British journal of pharmacology 20130101 2

<h4>Background and purpose</h4>Statin treatment may ameliorate viral infection-induced exacerbations of chronic obstructive pulmonary disease (COPD), which exhibit Th2-type bronchial inflammation. Thymic stromal lymphopoietin (TSLP), a hub cytokine switching on Th2 inflammation, is overproduced in viral and dsRNA-stimulated bronchial epithelial cells from COPD donors. Hence, TSLP may be causally involved in exacerbations. This study tests the hypothesis that simvastatin inhibits dsRNA-induced TS ...[more]

PMID: 22881993

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Project description:Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial.We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers.A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89).Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).

Dataset Information

Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Selective inhibition by simvastatin of IRF3 phosphorylation and TSLP production in dsRNA-challenged bronchial epithelial cells from COPD donors.

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