Intervening in
angiotensin (Ang)-II type 2 receptor (AT2) signaling may have therapeutic potential for
bronchopulmonary dysplasia (BPD) by attenuating
lung inflammation and preventing arterial
hypertension (PAH)-induced
right ventricular hypertrophy (RVH). We first investigated the role of AT2 inhibition with
PD123319 (0.5 and 2 mg·kg(-1)·day(-1)) on the beneficial effect of AT2 agonist LP2-3 (5 μg/kg twice a day) on RVH in newborn rats with
hyperoxia-induced BPD. Next we determined the cardiopulmonary effects of
PD123319 (0.1 mg·kg(-1)·day(-1)) in two models: early treatment during continuous exposure to
hyperoxia for 10 days and late treatment starting on day 6 in rat pups exposed postnatally to
hyperoxia for 9 days, followed by a 9-day recovery period in room air. Parameters investigated included lung and heart histopathology,
fibrin deposition, vascular leakage, and differential
mRNA expression. Ten days of coadministration of LP2-3 and
PD123319 abolished the beneficial effects of LP2-3 on RVH in experimental BPD. In the early treatment model
PD123319 attenuated cardiopulmonary injury by reducing alveolar septal thickness, pulmonary influx of inflammatory cells, including macrophages and neutrophils, medial wall thickness of small arterioles, and extravascular
collagen III deposition, and by preventing RVH. In the late treatment model
PD123319 diminished PAH and RVH, demonstrating that PAH is reversible in the neonatal period. At high concentrations
PD123319 blocks the beneficial effects of the AT2-agonist LP2-3 on RVH. At low concentrations
PD123319 attenuates cardiopulmonary injury by reducing
pulmonary inflammation and
fibrosis and preventing PAH-induced RVH but does not affect alveolar and vascular development in newborn rats with experimental BPD.