Sildenafil attenuates pulmonary inflammation and fibrin deposition, mortality and right ventricular hypertrophy in neonatal hyperoxic lung injury.
BACKGROUND
Phosphodiesterase-5 inhibition with sildenafil has been used to treat severe pulmonary hypertension and bronchopulmonary dysplasia (BPD), a chronic lung disease in very preterm infants who were mechanically ventilated for respiratory distress syndrome.


METHODS
Sildenafil treatment was investigated in 2 models of experimental BPD: a lethal neonatal model, in which rat pups were continuously exposed to hyperoxia and treated daily with sildenafil (50-150 mg/kg body weight/day; injected subcutaneously) and a neonatal lung injury-recovery model in which rat pups were exposed to hyperoxia for 9 days, followed by 9 days of recovery in room air and started sildenafil treatment on day 6 of hyperoxia exposure. Parameters investigated include survival, histopathology, fibrin deposition, alveolar vascular leakage, right ventricular hypertrophy, and differential mRNA expression in lung and heart tissue.


RESULTS
Prophylactic treatment with an optimal dose of sildenafil (2 x 50 mg/kg/day) significantly increased lung cGMP levels, prolonged median survival, reduced fibrin deposition, total protein content in bronchoalveolar lavage fluid, inflammation and septum thickness. Treatment with sildenafil partially corrected the differential mRNA expression of amphiregulin, plasminogen activator inhibitor-1, fibroblast growth factor receptor-4 and vascular endothelial growth factor receptor-2 in the lung and of brain and c-type natriuretic peptides and the natriuretic peptide receptors NPR-A, -B, and -C in the right ventricle. In the lethal and injury-recovery model we demonstrated improved alveolarization and angiogenesis by attenuating mean linear intercept and arteriolar wall thickness and increasing pulmonary blood vessel density, and right ventricular hypertrophy (RVH).


CONCLUSIONS
Sildenafil treatment, started simultaneously with exposure to hyperoxia after birth, prolongs survival, increases pulmonary cGMP levels, reduces the pulmonary inflammatory response, fibrin deposition and RVH, and stimulates alveolarization. Initiation of sildenafil treatment after hyperoxic lung injury and continued during room air recovery improves alveolarization and restores pulmonary angiogenesis and RVH in experimental BPD.
de Visser
Yvonne P
YP
Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, 2300 RC Leiden, the Netherlands. y.p.de_visser@lumc.nl
Walther
Frans J
FJ
Laghmani
El Houari
el H
Boersma
Hester
H
van der Laarse
Arnoud
A
Wagenaar
Gerry Tm
GT
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D018496:Hyperoxia / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D055370:Lung Injury / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage*; D011014:Pneumonia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D011687:Purines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000008:administration & dosage*; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D005337:Fibrin; D000068677:Sildenafil Citrate