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Open Access Highly Accessed Research

Roflumilast attenuates allergen-induced inflammation in mild asthmatic subjects

Gail M Gauvreau1*, Louis-Philippe Boulet2, Christine Schmid-Wirlitsch3, Johanne Côté2, MyLinh Duong1, Kieran J Killian1, Joanne Milot2, Francine Deschesnes2, Tara Strinich1, Richard M Watson1, Dirk Bredenbröker3 and Paul M O'Byrne1

Author Affiliations

1 Department of Medicine, McMaster University, Hamilton, Ontario, Canada

2 Institut Universitaire de Cardiologie et de Pneumologie de Québec, Quebec City, Quebec, Canada

3 NYCOMED GmbH, Konstanz, Germany

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Respiratory Research 2011, 12:140  doi:10.1186/1465-9921-12-140

Published: 26 October 2011

Abstract

Background

Phosphodiesterase 4 (PDE4) inhibitors increase intracellular cyclic adenosine monophosphate (cAMP), leading to regulation of inflammatory cell functions. Roflumilast is a potent and targeted PDE4 inhibitor. The objective of this study was to evaluate the effects of roflumilast on bronchoconstriction, airway hyperresponsiveness (AHR), and airway inflammation in mild asthmatic patients undergoing allergen inhalation challenge.

Methods

25 subjects with mild allergic asthma were randomized to oral roflumilast 500 mcg or placebo, once daily for 14 days in a double-blind, placebo-controlled, crossover study. Allergen challenge was performed on Day 14, and FEV1 was measured until 7 h post challenge. Methacholine challenge was performed on Days 1 (pre-dose), 13 (24 h pre-allergen), and 15 (24 h post-allergen), and sputum induction was performed on Days 1, 13, 14 (7 h post-allergen), and 15.

Results

Roflumilast inhibited the allergen-induced late phase response compared to placebo; maximum % fall in FEV1 (p = 0.02) and the area under the curve (p = 0.01). Roflumilast had a more impressive effect inhibiting allergen-induced sputum eosinophils, neutrophils, and eosinophil cationic protein (ECP) at 7 h post-allergen (all p = 0.02), and sputum neutrophils (p = 0.04), ECP (p = 0.02), neutrophil elastase (p = 0.0001) and AHR (p = 0.004) at 24 h post-allergen.

Conclusions

This study demonstrates a protective effect of roflumilast on allergen-induced airway inflammation. The observed attenuation of sputum eosinophils and neutrophils demonstrates the anti-inflammatory properties of PDE4 inhibition and supports the roles of both cell types in the development of late phase bronchoconstriction and AHR.

Trial Registration

ClinicalTrials.gov: NCT01365533

Keywords:
Allergic asthma; allergen challenge; PDE4 inhibitor; inflammation; sputum; neutrophils; eosinophils