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: Bodo Wonnenberg, Thomas Tschernig, Meike Voss, Markus Bischoff, Carola Meier, Stephan H Schirmer, Frank Langer, Robert Bals, Christoph Beisswenger
• Journal: International journal of medical microbiology : IJMM (Int J Med Microbiol) Vol. 304 Issue 5-6 Pg. 725-9 (Jul 2014) ISSN: 1618-0607 [Electronic] Germany
• PMID: 24938792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier GmbH. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Cytokines
• Uricosuric Agents
• Probenecid

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Cell Line
• Cytokines (metabolism)
• Disease Models, Animal
• Humans
• Inflammation (pathology, prevention & control)
• Mice, Inbred C57BL
• Pneumonia, Bacterial (pathology, prevention & control)
• Probenecid (therapeutic use)
• Pseudomonas Infections (pathology, prevention & control)
• Pseudomonas aeruginosa (isolation & purification)
• Uricosuric Agents (therapeutic use)