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. 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.

Amplification of the pulmonary vasodilatory response to inhaled iloprost by subthreshold phosphodiesterase types 3 and 4 inhibition in severe pulmonary hypertension.

OBJECTIVE: Aerosolized iloprost causes specific pulmonary vasodilation for about 60 mins in patients with severe primary and secondary pulmonary hypertension. Repeated daily inhalations are currently in use for chronic treatment. The aim of the current study was to evaluate if phosphodiesterase type 3 and 4 inhibition might amplify the prostanoid effect on pulmonary vasodilatation by stabilization of intracellular second messenger cyclic adenosine monophosphate. DESIGN: Uncontrolled clinical trial. SETTING: Medical intensive care unit, Department of Internal Medicine, University Hospital, Giessen, Germany. PATIENTS: A total of 11 patients with precapillary pulmonary hypertension (eight with primary pulmonary hypertension; one with pulmonary hypertension associated with calcinosis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia [CREST syndrome]; one with pulmonary hypertension associated with systemic lupus erythematodes, and one with chronic pulmonary embolism) were included. All were classified as New York Heart Association class III or class IV. INTERVENTIONS: During right heart catheterization, a single inhalation with iloprost (1.4 microg per inhalation) was performed, and hemodynamics and gas exchange variables were recorded for the next 2.5 hrs. After the iloprost effects had completely leveled off, the dual-selective phosphodiesterase types 3 and 4 inhibitor tolafentrine was infused in seven patients and aerosolized in five patients at doses that were per se ineffective (80 mg per 2.5 hrs intravenously; approximately 0.8 mg deposited by aerosol), followed by a second iloprost inhalation procedure. MEASUREMENTS: Decrease in pulmonary vascular resistance, duration of drug effect, safety, and tolerability of combined pharmacologic intervention. RESULTS: The decrease in pulmonary vascular resistance to sole iloprost nebulization lasted for approximately 60 mins. This response was enhanced and prolonged to approximately 120 mins in the presence of both infused and aerosolized tolafentrine, without loss of pulmonary selectivity. No adverse events were observed. CONCLUSIONS: These data support the principle that subthreshold selective phosphodiesterase types 3 and 4 inhibition amplifies the lung vasodilatory response to inhaled iloprost, with minute doses being sufficient via the inhalative route.