This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Objectives: The aim of this study was to explore the anti-inflammatory properties of roflumilast in a human model of segmental bronchial endotoxin challenge. A c c e p t e d m a n u s c r i p tMethods: In a randomized, placebo-controlled, double-blind, single-center parallelgroup study, 37 healthy subjects of either sex were treated for 28 days with either oral roflumilast 500 µg once daily or placebo. At Day 29, a baseline bronchoalveolar lavage was performed, followed by segmental endotoxin challenge (4 ng/kg) and saline control challenge.After 24 h, bronchoalveolar lavage fluid was sampled from the challenged segments and cells were counted and differentiated.Results: After endotoxin challenge, influx of total cells (difference from baseline) in bronchoalveolar lavage of roflumilast treated subjects was 36% lower than with placebo (p=0.02). Correspondingly, the influx of neutrophils and eosinophils of roflumilast treated subjects was 39% (p=0.02) and 74% (p=0.01) lower than with placebo, respectively. In contrast, endotoxin-induced influx of monocytes was not different between roflumilast and placebo treated subjects. No significant differences existed between the groups pertaining to endotoxin-induced influx of macrophages and lymphocytes. Roflumilast was well tolerated.No unexpected or serious treatment-emergent signs and symptoms were observed.Conclusions: Roflumilast attenuated the endotoxin-induced influx of neutrophils and eosinophils into the airways. This study demonstrates the anti-inflammatory properties of roflumilast on bronchoalveolar granulocytes in endotoxin-induced airway inflammation in healthy subjects. (Word count: 240 words)

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