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

Prophylactic benefits of systemically delivered simvastatin treatment in a house dust mite challenged murine model of allergic asthma

“…Interestingly, prophylactic treatment prevented the accumulation of anti-inflammatory IL-10 and the stereotypic Th2 cytokine, IL-4, 8 and 48 hours after HDM challenge but acute simvastatin therapy only slowed their accumulation as peak allergen-induced levels were still reached 48 hours after HDM challenge. This is inconsistent with some reports that simvastatin can upregulate IL-10 in human subjects with chronic obstructive lung disease (Maneechotesuwan et al, 2015). A limitation of our experiments is that though we observed a suppression of lymphocyte influx with simvastatin therapy, our cytokine array did not include IL-17, which is downregulated by statin treatment in ovalbumin-primed mice (Imamura et al, 2009;Wu et al, 2017).…”

Simvastatin up-regulates adenosine deaminase and suppresses osteopontin expression in COPD patients through an IL-13-dependent mechanism

“…This is supported by the recent study showing that statins significantly reduced airway and pulmonary neutrophils in stable COPD [34]. Our previous study also demonstrated that statin therapy could suppress IL-17 and restore IL-10 in COPD although this was associated with reduction in alveolar macrophages but not neutrophils as previously explained [29]. Therefore, statins may attenuate progressive decline in lung function although there have been very few studies investigating signaling molecules simultaneously involved in both inflammatory and fibrogenic activities including OPN and IL-13.…”

“…Simvastatin may suppress pro-inflammatory and induce anti-inflammatory cytokines in COPD [29]. Furthermore, simvastatin inhibits IL-13 inducible OPN gene in airway epithelial cells.…”

Protective Effects of Simvastatin and Hesperidin against Complete Freund's Adjuvant-Induced Rheumatoid Arthritis in Rats

“…Simvastatin was also reported to protect dopaminergic neurons in rats with experimentally induced Parkinsonism via suppression of TNF-α production [46] . Recently, simvastatin was reported to upregulate serum IL-10 in patients with stable chronic obstructive pulmonary disease [47] . A second explanation for the anti-arthritic effect of simvastatin may be attributed to its anti-inflammatory effect evident in the current study through the suppression of serum MPO and CRP levels.…”