title: Phosphodiesterase 4 inhibition attenuates persistent heart and lung injury by neonatal hyperoxia in rats.
abstract: Phosphodiesterase (PDE) 4 inhibitors are potent anti-inflammatory drugs with antihypertensive properties, and their therapeutic role in bronchopulmonary dysplasia (BPD) is still controversial. We studied the role of PDE4 inhibition with piclamilast on normal lung development and its therapeutic value on pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) in neonatal rats with hyperoxia-induced lung injury, a valuable model for premature infants with severe BPD. The cardiopulmonary effects of piclamilast treatment (5 mg·kg(-1)·day(-1)) were investigated in two models of experimental BPD: 1) daily treatment during continuous exposure to hyperoxia for 10 days; and 2) late treatment and injury-recovery in which pups were exposed to hyperoxia or room air for 9 days, followed by 9 or 42 days of recovery in room air combined with treatment started on day 6 of oxygen exposure until day 18. Prophylactic piclamilast treatment reduced pulmonary fibrin deposition, septum thickness, arteriolar wall thickness, arteriolar vascular smooth muscle cell proliferation and RVH, and prolonged survival. In the late treatment and injury-recovery model, hyperoxia caused persistent aberrant alveolar and vascular development, PH, and RVH. Treatment with piclamilast in both models reduced arteriolar wall thickness, attenuated RVH, and improved right ventricular function in the injury recovery model, but did not restore alveolarization or angiogenesis. Treatment with piclamilast did not show adverse cardiopulmonary effects in room air controls in both models. In conclusion, PDE4 inhibition attenuated and partially reversed PH and RVH, but did not advance alveolar development in neonatal rats with hyperoxic lung injury or affect normal lung and heart development.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Yvonne P
authors.initials: YP
authors.lastname: de Visser
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Walther
authors.forename: El Houari
authors.initials: el H
authors.lastname: Laghmani
authors.forename: Paul
authors.initials: P
authors.lastname: Steendijk
authors.forename: Maaike
authors.initials: M
authors.lastname: Middeldorp
authors.forename: Arnoud
authors.initials: A
authors.lastname: van der Laarse
authors.forename: Gerry T M
authors.initials: GT
authors.lastname: Wagenaar
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D001997:Bronchopulmonary Dysplasia / Q000188:drug therapy / Q000473:pathology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004195:Disease Models, Animal; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006335:Heart Injuries / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D018496:Hyperoxia / Q000188:drug therapy* / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000503:physiopathology; D007231:Infant, Newborn; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000254:growth & development; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats
chemical_list: D001549:Benzamides; D058988:Phosphodiesterase 4 Inhibitors; D011725:Pyridines; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D010100:Oxygen; C087566:piclamilast