Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia*

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

doi:10.1097/ccm.0b013e3181959814

Cited by 30 publications

(23 citation statements)

References 39 publications

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“…These results serve to confirm the emerging idea that PDE2A is a key proinflammatory enzyme that enhances the cellular and humoral inflammation associated with common forms of tissue injury (14,41,44,52).…”

Section: Discussionsupporting

confidence: 74%

“…Inhibition of eNOS, sGC, or PDE2A prevented endothelial barrier dysfunction whereas further enhancement of cGMP production with a direct sGC activator exacerbated the injury (39). More recently, an injurious role for increased lung PDE2A expression was found in a mouse model of pneumococcal pneumonia (52). Specifically, Streptococcus pneumoniae serotype-3 infection in intact mice was shown to increase PDE2A mRNA and protein at 24 h postinfection with no changes noted in mRNA for PDEs 3A, 3B, 4A, 4B, 4C, 4D, 5A, or 7A.…”

Section: Discussionmentioning

confidence: 92%

“…Specifically, Streptococcus pneumoniae serotype-3 infection in intact mice was shown to increase PDE2A mRNA and protein at 24 h postinfection with no changes noted in mRNA for PDEs 3A, 3B, 4A, 4B, 4C, 4D, 5A, or 7A. A continuous subcutaneous infusion of the PDE2A inhibitor hydroxyl-PDP inhibited a pneumonia-induced increase in BAL albumin but had no effect on the increased BAL neutrophils caused by pneumococcal infection (52).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, increased lung PDE2A expression was found in a murine model of pneumococcal pneumonia (52). In both studies, pharmacological PDE2A inhibition attenuated the associated ALI (39,52).On the basis of these observations, we hypothesized that IT LPS would potently increase lung PDE2A expression. Because of our observation regarding VILI-induced PDE2A upregulation (39), we wondered whether the combination of IT LPS and high tidal volume (HV T ) ventilation would produce a more severe injury through an increase in lung PDE2A expression.…”

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confidence: 99%

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confidence: 99%

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Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Rentsendorj

Damarla

Aggarwal

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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is stimulated by cGMP to hydrolyze cAMP, a potent endothelial barrier-protective molecule. We previously found that lung PDE2A contributed to a mouse model of ventilator-induced lung injury (VILI). The purpose of the present study was to determine the contribution of PDE2A in a two-hit mouse model of 1-day intratracheal (IT) LPS followed by 4 h of 20 ml/kg tidal volume ventilation. Compared with IT water controls, LPS alone (3.75 g/g body wt) increased lung PDE2A mRNA and protein expression by 6 h with a persistent increase in protein through day 4 before decreasing to control levels on days 6 and 10. Similar to the PDE2A time course, the peak in bronchoalveolar lavage (BAL) neutrophils, lactate dehydrogenase (LDH), and protein concentration also occurred on day 4 post-LPS. IT LPS (1 day) and VILI caused a threefold increase in lung PDE2A and inducible nitric oxide synthase (iNOS) and a 24-fold increase in BAL neutrophilia. Compared with a control adenovirus, PDE2A knockdown with an adenovirus expressing a short hairpin RNA administered IT 3 days before LPS/VILI effectively decreased lung PDE2A expression and significantly attenuated BAL neutrophilia, LDH, protein, and chemokine levels. PDE2A knockdown also reduced lung iNOS expression by 53%, increased lung cAMP by nearly twofold, and improved survival from 47 to 100%. We conclude that in a mouse model of LPS/VILI, a synergistic increase in lung PDE2A expression increased lung iNOS and alveolar inflammation and contributed significantly to the ensuing acute lung injury.lipopolysaccharide; ventilator-induced; cyclic guanosine monophosphate; inducible nitric oxide synthase; cAMP SEVERE PNEUMONIA IS A FREQUENT cause of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) (49). ARDS is characterized by neutrophil infiltration, the generation of toxic cytokines and reactive oxygen species (ROS), increased NO production and the loss of endothelial and epithelial barrier function (4). These features can be reproduced in animal models by the installation of intratracheal (IT) LPS (10, 24, 31), a key component of the gram-negative bacterial cell wall. LPS, through Toll-like receptor-4 signaling, was shown to cause increased NO from phosphorylated endothelial (eNOS) (11) and inducible nitric oxide synthase (iNOS) (24, 31) in alveolar macrophages, neutrophils, epithelium, and endothelium. NO from both eNOS and iNOS was found to play a major pathogenic role in ALI from LPS (24, 31, 42) and in ventilator-induced lung injury (VILI) (33, 39). These injurious effects of endogenous NO have been attributed to a reaction with superoxide to generate peroxynitrite (31, 33). In both LPS-induced ALI (47) and VILI (39), however, NO also activates soluble guanylyl cyclase (sGC), increasing production of cGMP in multiple cell types including endothelium (39), epithelium (9, 17), and macrophages (3).The effects of cGMP signaling in ALI are complex, depending on cell type, intracellular compartmentalization, and the downstream cGMP targets (39). These targets include...

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Rentsendorj

Damarla

Aggarwal

et al. 2011

American Journal of Physiology-Lung Cellular and Molecular Phys

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The Lung Endothelial Barrier in Acute Inflammation

Müller-Redetzky¹,

Lienau²,

Witzenrath³

2015

The Vertebrate Blood-Gas Barrier in Health and Disease

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Dynamics of pulmonary endothelial barrier function in acute inflammation: mechanisms and therapeutic perspectives

2014

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The lungs provide a large inner surface to guarantee respiration. In lung alveoli, a delicate membrane formed by endo- and epithelial cells with their fused basal lamina ensures rapid and effective gas exchange between alveolar and vascular compartments while concurrently forming a robust barrier against inhaled particles and microbes. However, upon infectious or sterile inflammatory stimulation, tightly regulated endothelial barrier leakiness is required for leukocyte transmigration. Further, endothelial barrier disruption may result in uncontrolled extravasation of protein-rich fluids. This brief review summarizes some important mechanisms of pulmonary endothelial barrier regulation and disruption, focusing on the role of specific cell populations, coagulation and complement cascades and mediators including angiopoietins, specific sphingolipids, adrenomedullin and reactive oxygen and nitrogen species for the regulation of pulmonary endothelial barrier function. Further, current therapeutic perspectives against development of lung injury are discussed.

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Phosphodiesterase 2 inhibition diminished acute lung injury in murine pneumococcal pneumonia*

Abstract: 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.

Cited by 30 publications

References 39 publications

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

The Lung Endothelial Barrier in Acute Inflammation

Dynamics of pulmonary endothelial barrier function in acute inflammation: mechanisms and therapeutic perspectives

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