Phosphodiesterase‐5 inhibition attenuates pulmonary inflammation and fibrin deposition, and prolongs survival in neonatal hyperoxic lung injury

NRF2 protects against oxidant-associated airway disorders via cytoprotective gene induction. To examine if NRF2 is an important determinant of respiratory syncytial virus (RSV) susceptibility after neonate lung injury, Nrf2-deficient (Nrf2−/−) and wild-type (Nrf2+/+) mice neonatally exposed to hyperoxia were infected with RSV. To investigate the prenatal antioxidant effect on neonatal oxidative lung injury, time-pregnant Nrf2−/−and Nrf2+/+mice were given an oral NRF2 agonist (sulforaphane) on embryonic days 11.5–17.5, and offspring were exposed to hyperoxia. Bronchoalveolar lavage and histopathologic analyses determined lung injury. cDNA microarray analyses were performed on placenta and neonatal lungs. RSV-induced pulmonary inflammation, injury, oxidation, and virus load were heightened in hyperoxia-exposed mice, and injury was more severe in hyperoxia-susceptible Nrf2−/− mice than in Nrf2+/+ mice. Maternal sulforaphane significantly alleviated hyperoxic lung injury in both neonate genotypes with more marked attenuation of severe neutrophilia, edema, oxidation, and alveolarization arrest in Nrf2−/− mice. Prenatal sulforaphane altered different genes with similar defensive functions (e.g., inhibition of cell/perinatal death and inflammation, potentiation of angiogenesis/organ development) in both strains, indicating compensatory transcriptome changes in Nrf2−/− mice. Conclusively, oxidative injury in underdeveloped lungs NRF2-dependently predisposed RSV susceptibility. In utero sulforaphane intervention suggested NRF2-dependent and -independent pulmonary protection mechanisms against early-life oxidant injury.

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Ambrisentan Prolongs Survival By Attenuating Pulmonary Hypertension, Fibrin Deposition And Right Ventricular Hypertrophy In Neonatal Hyperoxic Lung Injury

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a3941 ◽

2011 ◽

Author(s):

Gerry T. Wagenaar ◽

Yvonne P. de Visser ◽

El Houari Laghmani ◽

Frans J. Walther

Keyword(s):

Pulmonary Hypertension ◽

Lung Injury ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Right Ventricular Hypertrophy ◽

Fibrin Deposition ◽

Hyperoxic Lung Injury

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Inhaled nitric oxide attenuates pulmonary inflammation and fibrin deposition and prolongs survival in neonatal hyperoxic lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00381.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. L35-L44 ◽

Cited By ~ 40

Author(s):

Simone A. J. ter Horst ◽

Frans J. Walther ◽

Ben J. H. M. Poorthuis ◽

Pieter S. Hiemstra ◽

Gerry T. M. Wagenaar

Keyword(s):

Nitric Oxide ◽

Lung Injury ◽

Mrna Expression ◽

Plasminogen Activator ◽

Growth Factor Receptor ◽

Inhaled Nitric Oxide ◽

Lung Pathology ◽

Fibrin Deposition ◽

Plasminogen Activator Inhibitor 1 ◽

Hyperoxic Lung Injury

Administration of inhaled nitric oxide (iNO) is a potential therapeutic strategy to prevent bronchopulmonary dysplasia (BPD) in premature newborns with respiratory distress syndrome. We evaluated this approach in a rat model, in which premature pups were exposed to room air, hyperoxia, or a combination of hyperoxia and NO (8.5 and 17 ppm). We investigated the anti-inflammatory effects of prolonged iNO therapy by studying survival, histopathology, fibrin deposition, and differential mRNA expression (real-time RT-PCR) of key genes involved in the development of BPD. iNO therapy prolonged median survival 1.5 days ( P = 0.0003), reduced fibrin deposition in a dosage-dependent way up to 4.3-fold ( P < 0.001), improved alveolar development by reducing septal thickness, and reduced the influx of leukocytes. Analysis of mRNA expression revealed an iNO-induced downregulation of genes involved in inflammation (IL-6, cytokine-induced neutrophilic chemoattractant-1, and amphiregulin), coagulation, fibrinolysis (plasminogen activator inhibitor 1 and urokinase-type plasminogen activator receptor), cell cycle regulation (p21), and an upregulation of fibroblast growth factor receptor-4 (alveolar formation). We conclude that iNO therapy improves lung pathology and prolongs survival by reducing septum thickness, inhibiting inflammation, and reducing alveolar fibrin deposition in premature rat pups with neonatal hyperoxic lung injury.

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Pentoxifylline reduces fibrin deposition and prolongs survival in neonatal hyperoxic lung injury

Journal of Applied Physiology ◽

10.1152/japplphysiol.00452.2004 ◽

2004 ◽

Vol 97 (5) ◽

pp. 2014-2019 ◽

Cited By ~ 21

Author(s):

Simone A. J. ter Horst ◽

Gerry T. M. Wagenaar ◽

Eveline de Boer ◽

Margôt A. van Gastelen ◽

Joost C. M. Meijers ◽

...

Keyword(s):

Lung Injury ◽

Bronchoalveolar Lavage ◽

Total Protein ◽

Protein Concentration ◽

Bronchoalveolar Lavage Fluid ◽

Lavage Fluid ◽

Fibrin Deposition ◽

Total Protein Concentration ◽

Rat Pups ◽

Hyperoxic Lung Injury

Bronchopulmonary dysplasia is a leading cause of mortality and morbidity in preterm infants despite improved treatment modalities. Pentoxifylline, a phosphodiesterase inhibitor, inhibits multiple processes that lead to neonatal hyperoxic lung injury, including inflammation, coagulation, and edema. Using a preterm rat model, we investigated the effects of pentoxifylline on hyperoxia-induced lung injury and survival. Preterm rat pups were exposed to 100% oxygen and injected subcutaneously with 0.9% saline or 75 mg/kg pentoxifylline twice a day. On day 10, lung tissue was harvested for histology, fibrin deposition, and mRNA expression, and bronchoalveolar lavage fluid was collected for total protein concentration. Pentoxifylline treatment increased mean survival by 3 days ( P = 0.0018) and reduced fibrin deposition by 66% ( P < 0.001) in lung homogenates compared with untreated hyperoxia-exposed controls. Monocyte chemoattractant protein-1 expression in lung homogenates was decreased, but the expressions of TNF-α, IL-6, matrix metalloproteinase-12, tissue factor, and plasminogen activator inhibitor-1 were similar in both groups. Total protein concentration in bronchoalveolar lavage fluid was decreased by 33% ( P = 0.029) in the pentoxifylline group. Pentoxifylline treatment attenuates alveolar fibrin deposition and prolongs survival in preterm rat pups with neonatal hyperoxic lung injury, probably by reducing capillary-alveolar protein leakage.

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