title: Probenecid reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia.
abstract: The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia. This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P. aeruginosa lung infection. Pannexin-1 (Px1) channels mediate the activation of caspase-1 and release of IL-1β induced by P2X7 receptor activation. The approved drug probenecid is an inhibitor of Px1 and ATP release. In this study, we demonstrate that probenecid reduces infection and inflammation in acute P. aeruginosa pneumonia. Treatment of mice prior to infection with P. aeruginosa resulted in an enhanced clearance of P. aeruginosa and reduced levels of inflammatory mediators, such as IL-1β. In addition, probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells. Thus, Px1 blockade via probenecid treatment may be a therapeutic option in P. aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation.
authors.affiliation: Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, Germany.
authors.forename: Bodo
authors.initials: B
authors.lastname: Wonnenberg
authors.affiliation: Institute of Anatomy and Cell Biology, Saarland University, Homburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.affiliation: Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Voss
authors.affiliation: Institute of Medical Microbiology and Hygiene, Saarland University, Homburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Bischoff
authors.affiliation: Institute of Anatomy and Cell Biology, Saarland University, Homburg, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Meier
authors.affiliation: Department of Internal Medicine III, Saarland University Hospital, Homburg, Germany.
authors.forename: Stephan H
authors.initials: SH
authors.lastname: Schirmer
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Saarland University Hospital, Homburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Langer
authors.affiliation: Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Bals
authors.affiliation: Department of Internal Medicine V - Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Homburg, Germany. Electronic address: christoph.beisswenger@uks.eu.
authors.forename: Christoph
authors.initials: C
authors.lastname: Beisswenger
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D018410:Pneumonia, Bacterial / Q000473:pathology / Q000517:prevention & control*; D011339:Probenecid / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000473:pathology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000302:isolation & purification*; D014528:Uricosuric Agents / Q000627:therapeutic use*
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D014528:Uricosuric Agents; D011339:Probenecid
keywords: Hyperinflammation; Infection; Inflammation; Pannexin-1; Pneumonia; Probenecid