Simvastatin Suppresses Airway IL-17 and Upregulates IL-10 in Patients With Stable COPD

BACKGROUNDStatins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD, as has previously been demonstrated in patients with asthma.METHODSThirty patients with stable COPD were recruited to a double-blind, randomized, controlled, crossover trial comparing the effect of simvastatin, 20 mg po daily, with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was the presence of T-helper 17 cytokines and indoleamine 2,3-dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV1, and symptoms using the COPD Assessment Test (CAT).RESULTSAt 4 weeks, there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference, –16.4 pg/mL, P = .01; –48.6 pg/mL, P < .001; –45.3 pg/mL, P = .002; and –190.9 pg/mL, P = .007, respectively), whereas IL-10 concentrations, IDO messenger RNA expression (fold change), and IDO activity (kynurenine to tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference, 24.7 pg/mL, P < .001; 1.02, P < .001; and 0.47, P < .001, respectively). The absolute sputum macrophage count, proportion of macrophages, and CAT score were reduced after simvastatin compared with placebo (mean difference, –0.16 × 106Doe C Bafadhel M Siddiqui S et al.Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD.Chest. 2010; 138: 1140-1147Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, P = .004; –14.1%, P < .001; and –3.2, P = .02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments.CONCLUSIONSSimvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD.TRIAL REGISTRYClinicalTrials.gov; No.: NCT01944176; www.clinicaltrials.gov Statins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD, as has previously been demonstrated in patients with asthma. Thirty patients with stable COPD were recruited to a double-blind, randomized, controlled, crossover trial comparing the effect of simvastatin, 20 mg po daily, with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was the presence of T-helper 17 cytokines and indoleamine 2,3-dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV1, and symptoms using the COPD Assessment Test (CAT). At 4 weeks, there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference, –16.4 pg/mL, P = .01; –48.6 pg/mL, P < .001; –45.3 pg/mL, P = .002; and –190.9 pg/mL, P = .007, respectively), whereas IL-10 concentrations, IDO messenger RNA expression (fold change), and IDO activity (kynurenine to tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference, 24.7 pg/mL, P < .001; 1.02, P < .001; and 0.47, P < .001, respectively). The absolute sputum macrophage count, proportion of macrophages, and CAT score were reduced after simvastatin compared with placebo (mean difference, –0.16 × 106Doe C Bafadhel M Siddiqui S et al.Expression of the T helper 17-associated cytokines IL-17A and IL-17F in asthma and COPD.Chest. 2010; 138: 1140-1147Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, P = .004; –14.1%, P < .001; and –3.2, P = .02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments. Simvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD.