title: Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia.
abstract: 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.
  
  
  METHODS
  Controlled, in vitro, ex vivo, and in vivo laboratory study.
  
  
  METHODS
  Female Balb/C and C57Bl/6 mice, 8-12 weeks old.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Department of Internal Medicine/Infectious and Respiratory Diseases, Charité-Universitätsmedizin Berlin, Germany. martin.witzenrath@charite.de
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
authors.forename: Birgitt
authors.initials: B
authors.lastname: Gutbier
authors.forename: Bernd
authors.initials: B
authors.lastname: Schmeck
authors.forename: Herrmann
authors.initials: H
authors.lastname: Tenor
authors.forename: Joachim
authors.initials: J
authors.lastname: Seybold
authors.forename: Raimund
authors.initials: R
authors.lastname: Kuelzer
authors.forename: Guido
authors.initials: G
authors.lastname: Grentzmann
authors.forename: Armin
authors.initials: A
authors.lastname: Hatzelmann
authors.forename: Vincent
authors.initials: V
authors.lastname: van Laak
authors.forename: Thomas
authors.initials: T
authors.lastname: Tschernig
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Christian
authors.initials: C
authors.lastname: Schudt
authors.forename: Simone
authors.initials: S
authors.lastname: Rosseau
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.forename: Hartwig
authors.initials: H
authors.lastname: Schütte
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability; D002478:Cells, Cultured; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000150:complications*; D011650:Pulmonary Alveoli / Q000293:injuries; D012333:RNA, Messenger / Q000235:genetics; D012131:Respiratory Insufficiency / Q000209:etiology / Q000503:physiopathology
chemical_list: D012333:RNA, Messenger; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2