Roflumilast increases bacterial load and dissemination in a model of Pseudomononas aeruginosa airway infection

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Abstract

Exacerbations present a major clinical problem in many patients suffering from COPD. Roflumilast, an inhibitor of phosphodiesterase 4, has beneficial effects in several clinical trials and is currently widely used to prevent exacerbations in severe COPD. Roflumilast has anti-inflammatory properties that may interfere with potentially important host defense functions, including cytotoxic properties of neutrophils at sites of inflammation. Since chronic bacterial infection are prevalent in severe COPD, Pseudomonas aeruginosa being a major pathogen, we hypothesized that this drug could impair host defense against P. aeruginosa. In this study, mice were pretreated with vehicle alone or roflumilast at doses of 5 mg/kg or 10 mg/kg followed by instillation of P. aeruginosa in the airways. Bacterial load and dissemination as well as inflammatory markers and immune cells present in the airways were followed. Roflumilast increased mortality, bacterial load and dissemination in mice infected with P. aeruginosa. In addition, roflumilast-treated mice had significantly lower number of neutrophils in the bronchi but not in the lung tissue airways compared with untreated mice. Several proinflammatory cytokines decreased in roflumilast-treated mice but neither the neutrophil-recruiting chemokine KC nor IL-6. The findings show that roflumilast-treatment impair host defense against P. aeruginosa in the airways. This may imply that patients suffering from chronic bacterial infection of the airways could benefit from being withheld treatment with roflumilast.

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Subject classification (UKÄ) – MANDATORY

  • Respiratory Medicine and Allergy
  • Pharmacology and Toxicology
Original languageEnglish
Pages (from-to)66-72
JournalJournal of Pharmacology and Experimental Therapeutics
Volume357
Issue number1
Publication statusPublished - 2016
Publication categoryResearch
Peer-reviewedYes