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Phosphodiesterase‐5 inhibition attenuates pulmonary inflammation and fibrin deposition, and prolongs survival in neonatal hyperoxic lung injury
Author(s) -
Wagenaar Gerry T,
De Visser Yvonne P.,
Laghmani El Houari,
Boersma Hester,
Walther Frans J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.583
Subject(s) - bronchopulmonary dysplasia , bronchoalveolar lavage , medicine , hyperoxia , plasminogen activator , fibrin , lung , plasminogen activator inhibitor 1 , sildenafil , vascular endothelial growth factor , endocrinology , andrology , pathology , immunology , biology , pregnancy , genetics , vegf receptors , gestational age
Selective inhibition of phosphodiesterase‐5 by sildenafil is a potential therapeutic strategy to prevent or modify bronchopulmonary dysplasia (BPD) in very preterm infants. We evaluated this approach in a rat model, in which preterm pups were exposed to room air, hyperoxia or a combination of hyperoxia and sildenafil (50–150 mg/kg body weight/day; injected subcutaneously). The effects of prolonged sildenafil therapy were investigated by studying survival, histopathology, fibrin deposition (Western blotting), alveolar vascular leakage and differential mRNA expression ( real time RT‐PCR) of key genes involved in inflammation, coagulation, and alveolar enlargement after 10 days and survival. Treatment with sildenafil (2x 50 mg/kg/day) prolonged median survival up to 4 days ( p < 0.001), reduced fibrin deposition 2.7‐fold ( p < 0.01), total protein content in bronchoalveolar lavage fluid 2.1‐fold ( p < 0.05) and the influx of monocytes and macrophages 1.6‐fold ( p < 0.001) and neutrophils 3.1‐fold ( p < 0.001), and improved histopathology by reducing septum thickness and improving the mean linear intercept. Analysis of mRNA expression of key genes involved in experimental BPD revealed a significant sildenafil‐induced improvement of amphiregulin, plasminogen activator inhibitor‐1, fibroblast growth factor receptor‐4 and vascular endothelial growth factor receptor‐2. We conclude that PDE‐5 inhibition by sildenafil prolongs survival by reducing the inflammatory response, and improving lung histopathology in preterm rat pups with neonatal hyperoxic lung injury.