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

Abstract

Background: 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.

Methods: 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).

Results: 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 × 106, 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.

Conclusions: Simvastatin reversed the IL-17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD.

Trial registry: ClinicalTrials.gov; No.: NCT01944176; www.clinicaltrials.gov.

Figure 1 –

Flow of subjects through the study.

Figure 2 –

A, B, The lowering of sputum IL-17A (A) and IL-22 (B) concentrations in response to simvastatin treatment to a greater extent than placebo. Data are expressed as mean (SD). Δ = change in.

Figure 3 –

A, The elevation of sputum IL-10 concentrations was greater in response to simvastatin treatment than placebo. B, The same pattern was seen in IDO messenger RNA concentration. C, IDO activity also was elevated in response to simvastatin treatment to a greater extent than placebo. The data are expressed as mean (SD). IDO = indoleamine 2,3-dioxygenase; Kyn = kynurenine; Tryp = tryptophan. See Figure 2 legend for expansion of other abbreviation.

Figure 4 –

A, Sputum IL-6 concentration was lower in response to simvastatin treatment to a greater extent than placebo. B, The same pattern was seen in CXCL8 concentrations. The data are expressed as mean (SD). See Figure 2 legend for expansion of other abbreviation.

Figure 5 –

A, Absolute macrophage counts were lower in response to simvastatin treatment to a greater extent than placebo. B, A similar pattern was seen in the proportion of macrophages (% of total cells). The data are expressed as mean (SD).