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Published on: October 19, 2013
Phosphodiesterase 4 inhibition attenuates persistent heart and lung injury by neonatal hyperoxia in rats
Yvonne P de Visser1, Frans J Walther, El Houari Laghmani
1Department of Pediatrics, Division of Neonatology, Leiden University Medical Center, Leiden, the Netherlands.
Insights
Phosphodiesterase 4 (PDE4) inhibition with piclamilast reduced pulmonary hypertension and right ventricular hypertrophy in a neonatal rat model of bronchopulmonary dysplasia. However, it did not improve lung alveolar development.
Area of Science:
- Neonatal physiology and respiratory medicine
- Pharmacology and drug development
- Cardiopulmonary disease modeling
Background:
- Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants, often involving pulmonary hypertension (PH) and right ventricular hypertrophy (RVH).
- Phosphodiesterase 4 (PDE4) inhibitors are explored for anti-inflammatory and antihypertensive effects, but their role in BPD remains controversial.
- Hyperoxia-induced lung injury in neonatal rats serves as a relevant model for severe BPD.
Purpose of the Study:
- To investigate the therapeutic potential of PDE4 inhibition using piclamilast in neonatal rats with hyperoxia-induced lung injury.
- To evaluate the effects of piclamilast on lung development, pulmonary hypertension, and right ventricular hypertrophy.
- To assess the safety and efficacy of piclamilast in both prophylactic and late-stage treatment models.
Main Methods:
- Two models of experimental BPD were used: prophylactic treatment during 10 days of hyperoxia, and late treatment during a 9-day injury followed by recovery.
- Piclamilast (5 mg·kg(-1)·day(-1)) was administered, and cardiopulmonary effects were assessed.
- Measurements included pulmonary fibrin deposition, septum and arteriolar wall thickness, vascular smooth muscle cell proliferation, RVH, alveolarization, and angiogenesis.
Main Results:
- Prophylactic piclamilast treatment reduced lung injury markers, RVH, and improved survival.
- In the late treatment model, piclamilast attenuated arteriolar wall thickness and RVH, and improved right ventricular function, but did not restore alveolarization or angiogenesis.
- Piclamilast showed no adverse cardiopulmonary effects in normoxia control groups.
Conclusions:
- PDE4 inhibition with piclamilast can attenuate and partially reverse pulmonary hypertension and right ventricular hypertrophy in a neonatal rat model of lung injury.
- Piclamilast treatment did not promote alveolar development or angiogenesis in this model.
- PDE4 inhibition offers potential therapeutic benefits for specific aspects of BPD-related cardiopulmonary complications without negatively impacting normal development.
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.