Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia

Martin Witzenrath, Birgitt Gutbier, Bernd Schmeck, Herrmann Tenor, Joachim Seybold, Raimund Kuelzer, Guido Grentzmann, Armin Hatzelmann, Vincent van Laak, Thomas Tschernig, Timothy J Mitchell, Christian Schudt, Simone Rosseau, Norbert Suttorp, Hartwig Schütte

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)


OBJECTIVE: Severe pneumococcal pneumonia frequently causes respiratory failure. Both pathogen factors and an uncontrolled host response may contribute to acute lung injury by impairing microvascular barrier function. Phosphodiesterase 2 (PDE2) was examined as a potential target in pneumonia-induced lung microvascular hyperpermeability.

DESIGN: Controlled, in vitro, ex vivo, and in vivo laboratory study.

SUBJECTS: Female Balb/C and C57Bl/6 mice, 8-12 weeks old.

INTERVENTIONS: Human umbilical vein endothelial cells and isolated mouse lungs were challenged with the pneumococcal exotoxin pneumolysin in the presence or absence of the selective PDE2 inhibitors 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6one (PDP) or hydroxy-PDP. Transcellular electrical resistance or human serum albumin leakage in bronchoalveolar lavage fluid was determined, respectively. In addition, we induced pneumococcal pneumonia in mice and treated with hydroxy-PDP via continuous subcutaneous application by osmotic pumps. Human serum albumin leakage in bronchoalveolar lavage fluid was measured 48 hours after transnasal infection, and lung specimens were analyzed by TaqMan real-time polymerase chain reaction and Western blot for PDE2 gene and protein expression.

MEASUREMENTS AND MAIN RESULTS: In isolated perfused mouse lungs and in human umbilical vein endothelial cell monolayers, selective inhibition of PDE2 markedly decreased pneumolysin-induced hyperpermeability. Furthermore, in murine pneumococcal pneumonia, pulmonary PDE2-mRNA and -protein expression was significantly increased, and pneumonia-induced vascular permeability was distinctively reduced by PDE2 inhibition.

CONCLUSIONS: PDE2 inhibition diminished microvascular leakage in pneumococcal pneumonia, and pulmonary PDE2 upregulation may play a crucial role in this respect. Selective PDE2 inhibitors thus may offer a promising therapeutic approach in severe pneumococcal pneumonia.

Original languageEnglish
Pages (from-to)584-90
Number of pages7
JournalCritical care medicine
Issue number2
Publication statusPublished - Feb 2009


  • Acute Lung Injury
  • Animals
  • Bronchoalveolar Lavage Fluid
  • Capillary Permeability
  • Cells, Cultured
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Pneumonia, Pneumococcal
  • Pulmonary Alveoli
  • RNA, Messenger
  • Respiratory Insufficiency


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