Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia.
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.
Witzenrath
Martin
M
Department of Internal Medicine/Infectious and Respiratory Diseases, Charité-Universitätsmedizin Berlin, Germany. martin.witzenrath@charite.de
Gutbier
Birgitt
B
Schmeck
Bernd
B
Tenor
Herrmann
H
Seybold
Joachim
J
Kuelzer
Raimund
R
Grentzmann
Guido
G
Hatzelmann
Armin
A
van Laak
Vincent
V
Tschernig
Thomas
T
Mitchell
Timothy J
TJ
Schudt
Christian
C
Rosseau
Simone
S
Suttorp
Norbert
N
Schütte
Hartwig
H
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
D012333:RNA, Messenger; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2