Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia
Martin Witzenrath1, Birgitt Gutbier, Bernd Schmeck
1Department of Internal Medicine/Infectious and Respiratory Diseases, Charité-Universitätsmedizin Berlin, Germany. martin.witzenrath@charite.de
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.
Insights
Inhibiting phosphodiesterase 2 (PDE2) reduced lung microvascular leakage in severe pneumococcal pneumonia. This suggests PDE2 inhibitors could be a promising treatment for pneumonia-induced respiratory failure.
Area of Science:
- Pulmonary Medicine
- Vascular Biology
- Pharmacology
Background:
- Severe pneumococcal pneumonia can lead to respiratory failure due to impaired microvascular barrier function.
- Pathogen factors and host response contribute to acute lung injury in pneumonia.
- Phosphodiesterase 2 (PDE2) is investigated as a potential therapeutic target for pneumonia-induced lung microvascular hyperpermeability.
Purpose of the Study:
- To examine the role of phosphodiesterase 2 (PDE2) in pneumonia-induced lung microvascular hyperpermeability.
- To evaluate the efficacy of selective PDE2 inhibitors in reducing microvascular leakage during pneumococcal pneumonia.
Main Methods:
- In vitro, ex vivo, and in vivo laboratory studies were conducted.
- Human umbilical vein endothelial cells and isolated mouse lungs were challenged with pneumolysin, a pneumococcal exotoxin.
- Selective PDE2 inhibitors (PDP and hydroxy-PDP) were used to assess their effect on hyperpermeability in cell cultures and isolated lungs.
- Pneumococcal pneumonia was induced in mice, and treatment with hydroxy-PDP was administered to evaluate its impact on vascular permeability and PDE2 expression.
Main Results:
- Selective PDE2 inhibition significantly decreased pneumolysin-induced hyperpermeability in both isolated mouse lungs and human endothelial cell monolayers.
- Pulmonary PDE2 mRNA and protein expression were significantly increased in murine pneumococcal pneumonia.
- PDE2 inhibition distinctly reduced pneumonia-induced vascular permeability in mice.
Conclusions:
- PDE2 inhibition effectively diminished microvascular leakage in the context of pneumococcal pneumonia.
- Pulmonary PDE2 upregulation appears to play a critical role in pneumonia-induced vascular hyperpermeability.
- Selective PDE2 inhibitors represent a promising therapeutic strategy for managing severe pneumococcal pneumonia and preventing respiratory failure.
Related Concept Videos
01:29Pneumonia II: Pathophysiology
01:23Chronic Obstructive Pulmonary Disease II: Emphysema