title: Roflumilast Increases Bacterial Load and Dissemination in a Model of Pseudomononas Aeruginosa Airway Infection.
abstract: Exacerbations present a major clinical problem in many patients suffering from chronic obstructive pulmonary disease (COPD). Roflumilast, an inhibitor of phosphodiesterase 4, has shown 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 is 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 monitored. Roflumilast increased mortality, bacterial load, and dissemination in mice infected with P. aeruginosa. In addition, roflumilast-treated mice had significantly lower numbers 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 in neither the neutrophil-recruiting chemokine KC nor IL-6. These findings show that roflumilast treatment impairs host defense against P. aeruginosa in the airways, which may indicate that patients suffering from chronic bacterial infection of the airways could benefit from withholding of treatment with roflumilast.
authors: Respiratory Medicine & Allergology (G.K., R.K.V.B., A.E.) and Infection Medicine (P.P.), Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden Gopinath.Kasetty@med.lu.se.
authors: Gopinath
authors: G
authors: Kasetty
authors: Respiratory Medicine & Allergology (G.K., R.K.V.B., A.E.) and Infection Medicine (P.P.), Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
authors: Praveen
authors: P
authors: Papareddy
authors: Respiratory Medicine & Allergology (G.K., R.K.V.B., A.E.) and Infection Medicine (P.P.), Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
authors: Ravi K V
authors: RK
authors: Bhongir
authors: Respiratory Medicine & Allergology (G.K., R.K.V.B., A.E.) and Infection Medicine (P.P.), Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, Sweden.
authors: Arne
authors: A
authors: Egesten
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D058491:Bacterial Load / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018925:Chemokines / Q000378:metabolism; D015169:Colony Count, Microbial; D003521:Cyclopropanes / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils; D011552:Pseudomonas Infections / Q000382:microbiology* / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000382:microbiology*; D012141:Respiratory Tract Infections / Q000382:microbiology* / Q000473:pathology
chemical_list: D000631:Aminopyridines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D018925:Chemokines; D003521:Cyclopropanes; D016207:Cytokines; C424423:Roflumilast