Asthma and lower airway disease
Statins enhance the anti-inflammatory effects of inhaled corticosteroids in asthmatic patients through increased induction of indoleamine 2, 3-dioxygenase

https://doi.org/10.1016/j.jaci.2010.08.005Get rights and content

Background

We have previously shown that inhaled corticosteroids activate indoleamine 2, 3-dioxygenase (IDO) activity through increased IL-10 secretion. Statins might enhance the anti-inflammatory effects of corticosteroids.

Objective

In a double-blind study we added simvastatin to patients with mild asthma receiving a low dose of inhaled budesonide and evaluated sputum eosinophil counts, IL-10 secretion, and IDO activity, as well as their putative signaling pathways.

Methods

After a 2-week run-in period without treatment, 50 asthmatic patients were treated with 200 μg of budesonide and randomly assigned to either 10 mg of simvastatin or matched placebo for 8 weeks. Inflammation was evaluated through eosinophil counts, secretory signaling molecules, and immunocytochemistry of macrophages in sputum.

Results

Sputum eosinophil percentages were reduced significantly by the combined therapy with budesonide and simvastatin compared with budesonide alone (P = .02). Corticosteroids activated glucocorticoid-induced TNF receptor ligand, which induces activation of p52 through the noncanonical nuclear factor κB pathway, leading to the increased transcription and activation of IDO. Simvastatin enhanced corticosteroid-activated noncanonical nuclear factor κB–dependent induction of IDO by activating type I interferons and also enhanced the effect of corticosteroid on IL-10 release.

Conclusion

A statin enhances the anti-inflammatory effect of an inhaled corticosteroid in asthma, and this was mediated through the alteration of IDO activity in macrophages.

Section snippets

Patients

Nonsmoking patients with stable asthma were defined according to American Thoracic Society criteria and were treated with less than 1,000 μg/d beclomethasone dipropionate or an equivalent ICS. None of the patients had received oral corticosteroids within 3 months before the study. Subjects had a baseline FEV1 of 60% or greater of predicted value and demonstrated 12% or greater reversibility of FEV1 after therapy with nebulized salbutamol (2.5 mg) and a provocative concentration of methacholine

Patients

Of a total of 63 screened patients, 50 fulfilled the entry requirements and were randomized into either the simvastatin tablet group (n = 25) or the placebo group (n = 25; Fig 1, B, and Table I). Forty-seven patients completed the treatment phase, and 3 patients discontinued the study before completion, 3 in the simvastatin arm (2 were unable to provide adequate sputum and 1 had missing final lung function test data).

Simvastatin increases the anti-inflammatory effect of ICSs on eosinophilic airway inflammation in asthmatic patients

During the run-in off-treatment period, all patients had eosinophilic airway

Discussion

We conceived this randomized controlled study to verify whether a statin enhances the anti-inflammatory effects of an ICS in asthma. Here we have demonstrated that simvastatin increases the anti-inflammatory effect of inhaled budesonide in suppressing eosinophilic airway inflammation in asthmatic patients and that this is mediated through the activation of IDO through 2 distinct but interacting molecular pathways. First, corticosteroids induce IDO activation through the GITRL-associated

References (22)

  • P. Terness et al.

    Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites

    J Exp Med

    (2002)
  • Cited by (0)

    Supported by the Siriraj Grant for Research Development and Medical Education of the Faculty of Medicine Siriraj Hospital, Mahidol University.

    Disclosure of potential conflict of interest: P. J. Barnes has received research support from GlaxoSmithKline, AstraZeneca, and Novartis. The rest of the authors have declared that they have no conflict of interest.

    View full text